METHOD OF TREATING PATIENTS WITH A FACTOR Xa INHIBITOR, ASPIRIN, AND VERAPAMIL

ABSTRACT

The present disclosure in various embodiments teaches methods of treating patients in need of treatment with a Factor Xa inhibitor, and who are also concomitantly administered aspirin and verapamil.

CROSS-REFERENCE TO RELATED APPLICATION

The present Application is a continuation of U.S. application Ser. No.16/102,176, filed on Aug. 13, 2018, which is hereby incorporated byreference in its entirety herein.

BACKGROUND

Cardiovascular diseases and major cardiovascular events are a leadingcause of morbidity and mortality. Such disease and events are caused byabnormalities in haemostasis. Maintenance of normal haemostasis betweenbleeding and thrombosis is subject to complex regulatory mechanisms.Uncontrolled activation of the coagulant system or defective inhibitionof the activation processes may cause formation of local thrombi orembolisms in vessels (arteries, veins) or in heart cavities. This maylead to serious thromboembolic disorders, such as myocardial infarct,angina pectoris (including unstable angina), reocclusions and restenosesafter angioplasty or aortocoronary bypass, stroke, transitory ischaemicattacks, peripheral arterial occlusive disorders, pulmonary embolisms ordeep venous thromboses.

Cardiovascular diseases and events have traditionally been managed byantiplatelet therapies or anticoagulant therapies. Aspirin is known toreduce platelet aggregation. Specifically, aspirin irreversibly blocksthe formation of thromboxane A2, which reduces platelet aggregation. Assuch, aspirin reduces the risk of secondary ischemic events inindividuals who have experienced coronary artery disease (e.g., angina,myocardial infarct, peripheral artery disease, or cerebrovascularischemia). Aspirin also may reduce the risk of initial thrombotic eventsin healthy individuals who are at risk of suffering a majorcardiovascular event. For this reason, many individuals take aspirin ona regular basis for the primary or secondary prevention ofthromboembolic disease.

Unfortunately, aspirin only reduces platelet aggregation by blockingformation of thromboxane A2, and the coagulation cascade is a complexprocess that is mediated by numerous other factors. Furthermore, the useof aspirin can be accompanied by undesirable side effects includingmajor bleeding events (e.g., gastrointestinal bleeding).

Anticoagulant drugs target various procoagulant factors in thecoagulation pathway to reduce the risk of thrombotic disorders byreducing coagulation. One new class of anticoagulant drugs is Factor Xainhibitors, which play a central role in the cascade of bloodcoagulation by inhibiting Factor Xa directly.

Rivaroxaban is a Factor Xa inhibitor drug used to treat disordersincluding deep vein thrombosis (DVT) and pulmonary embolism (PE). It isalso used to help prevent strokes or serious blood clots in people whohave atrial fibrillation.

The use of rivaroxaban, however, presents considerable risk to patients.Because rivaroxaban reduces blood clotting, higher than expected bloodconcentrations of rivaroxaban can cause serious adverse events, mostnotably elevated rates of internal bleeding/hemorrhage. Conversely, anyunder dosing of the drug leaves a patient at risk of potentially fatalclotting events.

Because both aspirin and rivaroxaban, separately, present significantbleed risks, the combined use can be dangerous.

SUMMARY OF THE DISCLOSURE

In some embodiments, the present disclosure is directed to a method oftreating a patient in need of treatment with a Factor Xa (e.g.,rivaroxaban) inhibitor and who is concomitantly administered aspirin andverapamil, comprising administering a dose of rivaroxaban which is areduced dose relative to the dose recommended for an otherwise identical(or the same) patient who is not concomitantly administered aspirin andverapamil (e.g. about 99.5% to about 0% of the reference dose). Invarious embodiments, the patient in need of treatment with a Factor Xainhibitor has normal renal function, and in still other embodiments, thepatient has renal insufficiency (mild, moderate or severe as describedherein).

In some embodiments, the present disclosure is directed to a method oftreating a patient in need of treatment with rivaroxaban and who isconcomitantly administered aspirin and verapamil, comprisingadministering a reduced dose of rivaroxaban (e.g., reduced relative tothe reference dose) in an immediate release or rapid release formulationwhich achieves blood plasma concentrations described herein as safe(e.g., below that provided by a single 5 mg dose of rivaroxaban whenadministered in the absence of verapamil, or bioequivalent to thatprovided by a single 2.5 mg dose of rivaroxaban when administered in theabsence of verapamil). In various embodiments, the patient in need oftreatment with a Factor Xa inhibitor has normal renal function, and instill other embodiments, the patient has renal insufficiency (mild,moderate or severe as described herein).

In some embodiments, the present disclosure provides a method oftreating a patient with rivaroxaban, comprising (a) administering about100 to about 480 mg of verapamil daily to the patient; (b) administeringabout 75 mg to about 325 mg of aspirin to the patient; and (c)administering about 0.5 mg to less than about 2.5 mg of rivaroxaban tothe patient. In some embodiments, the dose of verapamil administered instep (a) is 120, 240, 360, or 480 mg. In some embodiments, the dose ofaspirin administered in step (b) is 100 mg. In some embodiments, thepatient is administered 100 mg of aspirin once daily. In someembodiments, the dose of rivaroxaban administered in step (c) rangesfrom 0.5 mg to about 2.0 mg of rivaroxaban (for example about 0.5 mg,about 0.75 mg, about 1.0 mg, about 1.25 mg, about 1.5 mg, about 1.75 mg,or about 2.0 mg). In some embodiments, the dose of rivaroxaban isadministered in an immediate release or rapid release formulation. Insome embodiments, the dose of rivaroxaban administered in step (c)ranges from about 15% to about 95% of the dose recommended for anotherwise identical patient who is not concomitantly administeredaspirin and verapamil.

In some embodiments, the present disclosure is directed to a method oftreating a patient concomitantly administered rivaroxaban, aspirin, andverapamil, wherein the dose of rivaroxaban administered to the patientis 15% to about 95% (e.g., about 15%, about 20%, about 25%, about 30%,about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about95%, inclusive of all values and subranges therebetween) of therivaroxaban dose recommended for the otherwise identical (or the same)patient who is not concomitantly administered verapamil.

In some embodiments, the patient is administered the dose rivaroxabantwice daily. In some embodiments, the total daily dose of rivaroxabanadministered to the patient is less than 5 mg (e.g., the total dailydose of rivaroxaban administered to the patient is about 0.5 mg, about0.75 mg, about 1.0 mg, about 1.25 mg, about 1.5 mg, about 1.75 mg, about2.0 mg, about 2.25 mg, about 2.5 mg, about 2.75 mg, about 3.0 mg, about3.25 mg, about 3.5 mg, about 3.75 mg, about 4.0 mg, about 4.25 mg, about4.5 mg, or about 4.75 mg).

In some embodiments, the patient has a C_(max) and AUC that isbioequivalent to a single 2.5 mg dose of rivaroxaban in an otherwiseidentical patient that was not coadministered verapamil. In someembodiments, the patient has a C_(max) and AUC below those provided byadministration of a single 5 mg dose of rivaroxaban in an otherwiseidentical patient that was not coadministered verapamil.

In some embodiments, the present disclosure provides a method oftreating a patient with rivaroxaban, wherein after administering thedose of rivaroxaban, the patient has at least one of the followingcharacteristics: (i) a geometric mean of an area under the plasmaconcentration-time curve (AUC) of rivaroxaban in the range of from about80% of about 165.4 μg·h/L to about 125% of about 551.9 μg·h/L after asingle dose of rivaroxaban; (ii) a geometric mean of a maximum bloodplasma concentration (C_(max)) of rivaroxaban in the range of from about80% of 28.6 μg/L to about 125% of 103.0 μg/L after a single dose ofrivaroxaban; (iii) a risk of major bleeding of no more than about 4.5%;and (iv) a prothrombin time of 20-30 seconds.

In some embodiments, the present disclosure provides a method oftreating a patient with rivaroxaban, wherein after administering thedose of rivaroxaban, the patient has at least one of the followingcharacteristics: (i) a geometric mean AUC of rivaroxaban that is lessthan 1064.25 μg·h/L after a single dose of rivaroxaban; and (ii) ageometric mean C_(max) of rivaroxaban that is less than 181.25 μg/Lafter a single dose of rivaroxaban; (iii) a risk of major bleeding of nomore than about 4.5%; and (iv) a prothrombin time of 20-30 seconds.

In some embodiments, the present disclosure is directed to a method oftreating a patient in need of treatment with a rivaroxaban and who isconcomitantly administered aspirin and verapamil, comprisingadministering a dose of rivaroxaban in an extended or delayed releaseformulation which maintains blood plasma concentrations described hereinas safe (e.g., blood plasma concentrations below those provided by a 5mg dose of rivaroxaban when administered in the absence of verapamil, orbioequivalent to those provided by a 2.5 mg dose of rivaroxaban whenadministered in the absence of verapamil). In various embodiments, thepatient in need of treatment with a Factor Xa inhibitor has normal renalfunction, and in still other embodiments, the patient has renalinsufficiency (mild, moderate or severe as described herein).

In some embodiments, the present disclosure is directed to a method oftreating a patient in need of treatment with rivaroxaban, comprising:(a) administering about 100 to about 480 mg of verapamil daily to thepatient; (b) administering about 75 mg to about 325 mg of aspirin to thepatient; and (c) administering less than about 5 mg of rivaroxaban(e.g., about 1.75 mg to less than 5 mg) to the patient once-daily,wherein at least a portion of the dose of rivaroxaban is administered ina delayed release or extended release component. In some embodiments,the dose of verapamil administered in step (a) is 120, 240, 360, or 480mg. In some embodiments, the dose of aspirin administered in step (b) is100 mg. In some embodiments, the patient is administered 100 mg ofaspirin once daily.

In some embodiments, the present disclosure is directed to a method oftreating patient concomitantly administered rivaroxaban, aspirin, andverapamil, wherein the dose of rivaroxaban administered to the patientis equal to the reference dose, but at least a portion of the dose ofrivaroxaban is administered in a delayed or extended releaseformulation. In such embodiments, the patient has a C_(max) and AUCbelow those corresponding to a 5 mg dose of rivaroxaban administered BIDin an otherwise identical patient that was not coadministered verapamil.In particular embodiments, the patient has a C_(max) and AUC that isbioequivalent to those provided by a 2.5 mg dose of rivaroxabanadministered BID in an otherwise identical patient that was notcoadministered verapamil.

In some embodiments, after administering a delayed release or extendedrelease formulation of rivaroxaban, the patient has at least one of thefollowing characteristics: (i) a geometric mean of an area under theplasma concentration-time curve (AUC) of rivaroxaban that is within therange of about 80%-125% of the AUC measured for an otherwise identicalpatient that was administered 2.5 mg of rivaroxaban, twice daily, butwas not administered verapamil; (ii) a geometric mean of a maximum bloodplasma concentration (C_(max)) of rivaroxaban in the range of from about80% of 28.6 μg/L to about 125% of 103.0 μg/L after a single dose ofrivaroxaban; (iii) a risk of major bleeding of no more than about 4.5%;and (iv) a prothrombin time of 20-30 seconds.

In some embodiments disclosed herein, the patient who is administeredrivaroxaban in an extended or delayed release formulation (concomitantlywith verapamil and aspirin according to the methods described herein)has a C_(max) of rivaroxaban (e.g., after a single dose) that is no morethan about 181.25 ng/mL. In some embodiments disclosed herein, theC_(max) of rivaroxaban (after a single dose) in said patient is in therange of from about 80% of 28.6 μg/L to about 125% of 103.0 μg/L after asingle dose of rivaroxaban.

In some embodiments disclosed herein, the patient who is administeredrivaroxaban in an extended or delayed release formulation (concomitantlywith verapamil and aspirin according to the methods described herein)has an AUC (after a single dose) in said patient which is less than2,128.5 μg·h/L. In some embodiments disclosed herein, the AUC (after asingle dose) in said patient is in the range of about 80% of about 330.8μg·h/L to about 125% of about 1,103.8 μg·h/L after a single dose ofrivaroxaban.

In some embodiments, the present disclosure is directed to a method oftreating a patient in need of treatment with a Factor Xa inhibitor,e.g., a patient with renal insufficiency (mild, moderate or severe asdescribed herein) comprising administering a dose of rivaroxaban whichis a reduced dose (e.g., about 99.5% to about 0%) relative to the doserecommended for an otherwise identical (or the same) patient who doesnot have renal insufficiency. In some embodiments, the patient isadministered about 0.5 mg to less than 2.5 mg of rivaroxaban in animmediate release or rapid release formulation, or less than about 5 mg(e.g., about 1.25 to less than 5 mg) in an extended release or delayedrelease formulation.

In some embodiments, the present disclosure is directed to treatment ofa patient with a medical condition requiring treatment with aspirin (inconjunction with verapamil and a Factor Xa inhibitor), where the purposeof treatment is selected from the group consisting of decreasing therisk of major cardiovascular events (death, myocardial infarction, orstroke) in patients with chronic coronary and/or peripheral arterydisease, reducing the risk of acute limb ischemia in patients withperipheral artery disease, decreasing the risk of major cardiovascularevents (death, myocardial infarction, or stroke) in patients with acutecoronary syndrome, and prevention and treatment of venousthromboembolism in cancer patients or patients with active cancer (alsoreferred to as cancer-associated venous thromboembolism).

In some embodiments, the patient experiences an increase in the risk ofinternal bleeding of no more than about 5% (e.g., about 5%, about 4.5%,about 4%, about 3.5%, about 3%, about 2.5%, about 2%, about 1.5%, andabout 1%, inclusive of all values and subranges therein) compared to anotherwise identical patient that was administered aspirin alone. In someembodiments, the patient's risk of a major bleeding event is less thanabout 5%. In some embodiments, the efficacy in treating the condition issimilar to the efficacy observed for the same condition in an otherwiseidentical patient that was treated with 2.5 mg of rivaroxaban but wasnot treated with verapamil.

In any of the various embodiments disclosed herein, the patient who isconcomitantly administered rivaroxaban, aspirin, and verapamil can havenormal renal function.

In any of the various embodiments disclosed herein, the patient who isconcomitantly administered rivaroxaban, aspirin, and verapamil can bemildly renally impaired.

In any of the various embodiments disclosed herein, the patient who isconcomitantly administered rivaroxaban, aspirin, and verapamil can havemoderate renal impairment.

In any of the various embodiments disclosed herein, the patient who isconcomitantly administered rivaroxaban, aspirin, and verapamil can havesevere renal impairment.

In any of the various embodiments disclosed herein, the maximumprothrombin time of said patient concomitantly administered rivaroxaban,aspirin, and verapamil ranges from about 20 to about 30 seconds.

In some embodiments, the patient has a CL_(Cr) of less than or equal toabout 89 mL/min. In some embodiments, the patient has a CL_(Cr) of lessthan or equal to about 79 mL/min. In some embodiments, the patient has aCL_(Cr) of 60-89 mL/min. In some embodiments, the patient has a CL_(Cr)of 30-59 mL/min. In some embodiments, the patient has a CL_(Cr) of 15-29mL/min.

In some embodiments disclosed herein, the patient who is concomitantlyadministered rivaroxaban, aspirin, and verapamil is not renallyimpaired. In some embodiments disclosed herein, the patient who isconcomitantly administered rivaroxaban, aspirin, and verapamil is mildlyrenally impaired. In some embodiments disclosed herein, the patient whois concomitantly administered rivaroxaban, aspirin, and verapamil ismoderately renally impaired. In some embodiments disclosed herein, thepatient who is concomitantly administered rivaroxaban, aspirin, andverapamil is severely renally impaired.

In some embodiments disclosed herein, the dose of rivaroxabanadministered to the patient who is concomitantly administeredrivaroxaban, aspirin, and verapamil is selected to generate aprothrombin time of said patient ranging from about 20-30 seconds. Instill further embodiments, the dose of rivaroxaban is less than 2.5 mg,and the rivaroxaban is administered in an immediate release or rapidrelease composition. In still further embodiments, the dose ofrivaroxaban is about 1.25 mg, and the rivaroxaban is administered in animmediate release or rapid release composition.

In some embodiments, the dose of rivaroxaban administered in the methodof the present invention is such that the AUC (AUC_(inf), AUC_(ss), orAUC for a single dose) and/or C_(max) (C_(max) for a single dose orsteady state) values of rivaroxaban in the treated patient populationdoes not exceed target values, e.g., the AUC and C_(max) values measuredfor a patient administered a 2.5 mg dose of rivaroxaban in the presenceof aspirin but not verapamil. The rivaroxaban dose is designed such thata particular statistical PK parameter characterizing the particularpatient population (e.g., maximum, mean of highest 3 patients, 90%confidence interval upper boundary, median, arithmetic mean, geometricmean, 90% confidence level lower boundary, or minimum of the AUC_(inf)and/or C_(max,)) does not exceed the selected target value. So, forexample, for a patient concomitantly administered rivaroxaban, aspirin,and verapamil, the dose of rivaroxaban intended to provide an AUC ofless than 1064.25 μg·hr/L for the patient in a population with thehighest exposure (“maximum”) would be a dose of no more than 2.5 mgrivaroxaban (e.g., about 1.75 mg rivaroxaban in an immediate releaseformulation, or an extended release formulation having a release profilethat achieves blood plasma levels approximately corresponding to a 2.5mg dose of rivaroxaban in a patient that was not concomitantly treatedwith verapamil).

In some embodiments, the present disclosure is directed to treating apatient in need of treatment with rivaroxaban and aspirin, wherein thepatient is not concomitantly administered verapamil (i.e., thecoadministration of rivaroxaban and verapamil is contraindicated forsuch patients). That is, in some embodiments, present methods aredirected to treating a patient in need of treatment with rivaroxaban andwho is concomitantly administered aspirin and verapamil, wherein thepatient ceases administration of verapamil and then is administeredrivaroxaban. In alternative embodiments, the patient is currently beingtreated with rivaroxaban and aspirin, and is in need of treatment withverapamil. In such embodiments, the patient ceases treatment withrivaroxaban and then is administered verapamil. In various embodiments,the patient has normal renal function, or in other embodiments, thepatient has renal insufficiency (mild, moderate or severe as describedherein).

BRIEF DESCRIPTIONS OF THE FIGURES

FIG. 1 shows a correlation between plasma concentrations of rivaroxabanand Prothrombin Time (“PT”) in subjects with no renal insufficiency.Data were measured on Day 1 and Day 15 of the study.

FIG. 2 shows a correlation between plasma concentrations of rivaroxabanand PT in subjects with mild renal insufficiency. Data were measured onDay 1 and Day 15 of the study.

FIG. 3 shows the ranges of steady state rivaroxaban AUC values forvarious single dose rivaroxaban treatments (10842, 10993, 10999, 12359,12680, 11273, 10989, 11938, studies), and single dose rivaroxaban plusverapamil treatments. Abbreviations in the figure are N: Normal renalfunction; MRI: mild renal impairment; P1: 20 mg rivaroxaban only; P3: 20mg rivaroxaban and 360 mg verapamil. The lines represent the geometricmean and for the numbered studies the top and bottom represent+/−1standard deviation. For the Normal and MRI groups by study period, thelines represent the geometric mean and the top and bottom represent thesample maximum and minimum.

FIG. 4 shows the 90% confidence level rivaroxaban AUC value (single 20mg dose) (Label “A”), steady state rivaroxaban AUC value as described inthe Clinical Pharmacology approval documents for rivaroxaban andseparately the 10 mg steady state dose in the presence of a strongCYP3A4/Pgp inhibitor (Label “B”) from the same report. The third item,(Label “C”) shows the upper 90% confidence interval value forrivaroxaban administered under fed conditions as determined in clinicalstudy 10989. These values are compared to the ranges of AUC measured bythe present inventors under various conditions. Abbreviations in thefigure are SS: steady state; CI: confidence interval; AUC inf: areaunder the curve extrapolated to infinity; N: Normal renal function; MRI:mild renal impairment; P1: a single 20 mg rivaroxaban only; P3: a single20 mg rivaroxaban plus 360 mg verapamil.

FIG. 5 shows the relationship between the steady state AUC values andthe risk of major bleeding. See Center for Drug Evaluation and Research,Application No. 022406Orig1s000, Clinical Pharmacology andBiopharmaceutics Review(s), at page 36, which is hereby incorporated byreference in its entirety.

DETAILED DESCRIPTION

While the following terms are believed to be well understood by one ofordinary skill in the art, the following definitions are set forth tofacilitate explanation of the presently disclosed subject matter.

Throughout the disclosure, singular forms such as “a,” “an,” and “the”are often used for convenience. However, it should be understood thatthe singular forms are intended to include the plural, except whencontext or an explicit statement indicates that the singular alone isintended.

Throughout this application, the term “about” is used to indicate that avalue includes the inherent variation of error for the device or themethod being employed to determine the value, or the variation thatexists among the samples being measured. In some embodiments, the term“about” means within 5% of the reported numerical value. When used inconjunction with a range or series of values, the term “about” appliesto the endpoints of the range or each of the values enumerated in theseries, unless otherwise indicated.

As used herein, the term “concomitant” refers to the co-administrationof two or more drugs. In some embodiments, concomitant administrationincludes the administration of two or more drugs at substantially thesame time, either as a mixture (e.g., in a coformulation), or asseparate doses. In some embodiments, concomitant administration alsoincludes the sequential administration of two or more drugs, whereinboth drugs are simultaneously present at clinically relevant levels in apatient's plasma.

As used herein, the term “pharmacokinetics” refers to a drug's movementinto, through, and out of the body, including: the drug's absorption,bioavailability, tissue distribution, metabolism, and excretion.

As used herein, C_(max) refers to peak plasma concentration of atherapeutic agent as it relates to a particular drug dose (e.g.rivaroxaban dose).

As used herein. T_(max) refers to the time required to reach peakconcentration.

As used herein, C_(ave) refers to average plasma concentration of atherapeutic agent under a particular drug dosing schedule (e.g.rivaroxaban dosing schedule).

As used herein, C_(min) refers to the minimum plasma concentration of atherapeutic agent under a particular drug dosing schedule (e.g.rivaroxaban dosing schedule).

In some embodiments, the present disclosure teaches that thepharmacokinetic effects of a drug can be compared based on area underthe curve (AUC) values. The pharmacokinetic AUC of a drug is calculatedby taking the integral (area under the curve) of the concentration of adrug against time.

As used herein, “treating” in the context of treating a condition refersto reducing or eliminating the symptoms of a condition, reducing therisk of, or preventing the patient from experiencing the symptoms of acondition. For example, treatment of a condition with rivaroxaban canreduce the risk of stroke or systemic embolism in patients, reducing therisk of recurrence of deep vein thrombosis and pulmonary embolism, theprophylaxis of deep vein thrombosis, etc.

As used herein, AUC_(0-∞) or AUC_(inf) refers to the area under thecurve extrapolated to infinity, after administration of a single dose ofdrug. AUC_(ss) refers to the AUC under steady state conditions, andapproximates AUC_(inf).

As used herein, the term “pharmacodynamics” refers to a drug's effect(s)on the body, including: receptor binding, postreceptor effects, andchemical interactions. In some embodiments, a drug's pharmacodynamicsdetermines the onset, duration, and intensity of that drug's effect.

As used herein, the term “major bleeding” or “major bleeding event”refers to a fatal bleeding event or an overt internal bleeding eventwith a corresponding drop in hemoglobin levels. The internal bleedingtypically occurs at a critical site, including gastrointestinal,intracranial, intraocular, intraspinal, intra-articular, intramuscularwith compartment syndrome, and pericardial, retroperitoneal. Thedecrease in hemoglobin may be at least about 1 g/dl, at least about 1.5g/dl, at least about 2 g/dl, at least about 2.5 g/dl, at least about 3g/dl, at least about 3.5 g/dl, at least about 4 g/dl, at least about 4.5g/dl, at least about 5 g/dl, at least about 5.5 g/dl, at least about 6g/dl, at least about 6.5 g/dl, or more. In some embodiments, majorbleeding is defined by the International Society on Thrombosis andHaemostasis (ISTH) criteria of overt bleeding accompanied by a decreasein the hemoglobin level of at least 2 g/dl or transfusion of at least 2units of packed red cells, occurring at a critical site (intracranial,intraocular, intraspinal, intra-articular, intramuscular withcompartment syndrome, pericardial, retroperitoneal), or resulting indeath. In some embodiments, major bleeding is defined by theThrombolysis in Myocardial Infarction (TIMI) criteria, which definesmajor bleeding as an intracranial haemorrhage, a decrease in hematocritof 15%, or a 5 g/dl decrease in the haemoglobin concentration.

As used herein, the term “prothrombin time” (PT) refers to a blood testthat measures how long it takes blood to clot. In some embodiments, aprothrombin time test can be used to measure of a patient's haemostasis.In some embodiments, PT can be used to measure the effectiveness orexposure to a blood clotting drug. Persons having skill in the artsometimes interchangeably refer to a PT test as an INR. However, sincethe INR is calibrated specifically for warfarin, PT measurementssuitable for rivaroxaban would not be comparable to the INR standardsfor warfarin. Additionally, PT measurements are subject to variabilitybased on the test reagent and laboratory test ranges determined by eachinstitution.

As used herein, the term “immediate release” refers to oralformulations, such as tablets and capsules, which are formulated torelease rivaroxaban immediately after oral administration. In suchformulations, no deliberate effort is made to modify the rate of drugrelease. Immediate release and instant release may be usedinterchangeably herein.

As used herein, the term “rapid release” has the same definition as usedin U.S. Pat. No. 9,539,218, and refers to a composition (e.g., tablet)which has a Q value (30 minutes) of 75% according to USP release methodusing apparatus 2 (paddle).

As used herein, “BID” refers to twice-daily administration.

As used herein, “extended release” refers to a pharmaceuticalformulation which releases the active agent (e.g., rivaroxaban) over anextended period of time. An extended period of time is longer than thatof the immediate release component as described herein, such that thetotal amount of active agent in an extended release component isreleased over a period of about 1 to 24 hours, e.g., over about 1 hour,about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours,about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours,about 20 hours, about 21 hours, about 22 hours, about 23 hours, or about24 hours, inclusive of all ranges between any of these values. In someembodiments, an extended release formulation may also include animmediate release component.

As used herein, “delayed release” refers to a pharmaceutical formulationwhich substantially prevents the release (meaning releasing no more thanabout 5-10%) of rivaroxaban contained in the delayed release componentfor a defined period of time after oral administration. In someembodiments, delayed release substantially prevents release of theactive for at least 30 minutes after oral administration, e.g., 35minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, 60 minutes, 65minutes, 70 minutes, 75 minutes, 80 minutes, 85 minutes, 90 minutes, 95minutes, 100 minutes, 105 minutes, 110 minutes, 115 minutes, 120minutes, about 3 hours, about 4 hours, about 5 hours, about 6 hours,about 7 hours, about 8 hours, or more. In some embodiments, delayedrelease also encompasses formulations in which a portion of the active(e.g., rivaroxaban) is not released from the formulation for aparticular period of time. That is, a delayed release formulation mayalso include an immediate release component. For example, in someembodiments, the delayed release component can substantially preventrelease of at least about 40% (e.g., about 40% to about 60%) of thetotal amount of rivaroxaban in the pharmaceutical formulation for atleast about 30 minutes after oral administration, e.g., 35 minutes, 40minutes, 45 minutes, 50 minutes, 55 minutes, 60 minutes, 65 minutes, 70minutes, 75 minutes, 80 minutes, 85 minutes, 90 minutes, 95 minutes, 100minutes, 105 minutes, 110 minutes, 115 minutes, 120 minutes, about 3hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about8 hours, or more.

Rivaroxaban was developed with the premise that it would not require thetype of monitoring required for conventional anticoagulant drugs such aswarfarin (Coumadin). PT/INR tests are conventionally used specificallyfor monitoring vitamin K antagonists such as warfarin. Alternativetests, such as the activated partial thromboplastin time (APTT) areconventionally used to monitor the use of unfractionated heparin.However, as discussed in Favaloro et al., Biochemia Medica 2012; 22(3):329-41, the PT/INR and APTT tests are not suitable for monitoringpatients treated with rivaroxaban because inconsistent results areobtained for rivaroxaban depending on factors such as the reagents used,and the tests are either too sensitive or insensitive to be useful. Inaddition, such tests are not calibrated for rivaroxaban, and thereforethere is no standardized measure for the activity of rivaroxaban in suchpatients. While the literature suggests that suitable tests could bedeveloped, presently there are no validated or generally recognizedmethods suitable for monitoring the use of rivaroxaban in hospitallaboratories or available to healthcare providers. See also, Xarelto®Package Insert (Revised August 2016, section 5.7). Consequently, thereare no current methods available for monitoring the dose titration ofrivaroxaban. Indeed, the sponsor of the rivaroxaban NDA maintains thatdose titration is not appropriate in most patient populations(Application Number: 022406Orig1s000 Clinical Pharmacology andBiopharmaceutics Review(s), Addendum to Apr. 6, 2009 Review). SeeHillarp et al., Journal of Thrombosis and Haemostasis, 9: 133-139;Favarolo et al., Biochemia Medica 2012; 22(3): 329-41; Nielsen et al.,Clin. Res. Cardiol. 22 Nov. 2014 (published online); and Mueck et al.,Clin. Pharmacokinet (2014) 53:1-16.

As used herein, E_(max) refers to peak effect of a therapeutic agentrelated to a particular drug dose (e.g. rivaroxaban dose).

As used herein, the term “AUEC” refers to area under the effect curve.In some embodiments, the pharmacodynamic AUEC of an effect for aparticular drug is calculated by taking the integral (area under thecurve) of the drug's measured effect against time.

In some embodiments, the AUEC of rivaroxaban is calculated based on theintegral of the prothrombin time effect a rivaroxaban dose has on apatient over time.

As used herein, “renal impairment” means the individual has a clinicallyrelevant level of renal function which is less than levels of renalfunction generally considered to be normal. Levels of renal function,renal sufficiency or renal impairment can be determined using any of themethods known in the art or described herein. Currently, one commonmethod for determining the level of renal sufficiency in an individualis determining creatinine clearance (CL_(Cr)) in the individual usingthe Cockcroft-Gault equation. In some embodiments, the presentdisclosure teaches alternative methods of measuring renal impairment,for example those described in U.S. Published App. 2012/022787.

As disclosed herein, the individual's actual body weight, ideal bodyweight, or otherwise adjusted body weight can be used in the equation.In some embodiments, the following are criteria for determining thelevel of renal sufficiency using creatinine clearance (CL_(Cr)) and theCockcroft-Gault equation:

Normal renal function> or =80 mL/min

Mild renal impairment=50-79 mL/min

Moderate renal impairment=30-49 mL/min

Severe renal impairment<30 mL/min

Newer criteria for determining the level of renal sufficiency usingCL_(Cr) define the cut-offs between normal, and mild-severe renalimpairment using slightly different CL_(Cr) ranges:

Normal renal function> or =90 mL/min

Mild renal impairment=60-89 mL/min

Moderate renal impairment=30-59 mL/min

Severe renal impairment=15-29 mL/min

Kidney failure<15 mL/min

A “patient” is a living organism, typically a human.

For nearly all FDA approved drugs, the “recommended” dose or “reference”dose (or doses) of the drug are determined based on the plasma level (orrange of plasma levels) of the drug required to provide the desiredclinical effect(s) and/or avoid undesirable side effects. Therecommended dose(s) of a particular drug are those recognized in the artas suitable for treating a patient with particular physicalcharacteristics (or within a range of particular characteristics), andare thus the dose(s) provided in the package insert for the drug. Thus,in various embodiments, the methods of the present disclosure aredirected to adjustments or changes in the dosing of rivaroxaban relativeto the FDA “recommended” dose, e.g., in the package insert forrivaroxaban, as suitable for treating a patient with particular physicalcharacteristics. Thus, as used herein, the “recommended dose” forrivaroxaban is distinct from doses which may be disclosed by particularphysicians for particular patients. Depending on the specificpharmacokinetics and pharmacodynamics of the drug, the recommended dosemay vary depending on one or more physical characteristics of thepatient, for example age, gender, weight, body mass index, livermetabolic enzyme status (e.g., poor or extensive metabolizer status),disease state, etc. Xarelto® (rivaroxaban) is currently sold in threeFDA-approved doses: 10 mg (e.g., NDC 50458-580-30), 15 mg (e.g.,NDC-50458-578-30), and 20 mg (e.g., NDC 50458-579-30). As discussed inmore detail herein, a twice daily dose of a 2.5 mg dose of rivaroxabanis currently being recommended in combination with aspirin.

The present disclosure provides for methods of treating patients withaspirin, rivaroxaban, and verapamil, and requires an adjustment of therivaroxaban dose relative to the recommended dose in that patient if thepatient was not concomitantly administered verapamil. A low dose ofaspirin in combination with a low dose of rivaroxaban has beendiscovered to reduce the risks of major cardiovascular events inpatients with clotting disorders or patients that are at risk ofdeveloping clotting disorders. For patients concomitantly administeredrivaroxaban and verapamil, a common drug used to treat atrialfibrillation a disease common to patients with clotting disorders andare thus on antiplatelet and/or anticoagulant therapies the inventorssurprisingly discovered that verapamil increases exposure to rivaroxabanto dangerous levels and may cause a significant risk of internalbleeding. As such, the inventors discovered that the dose of rivaroxabanmust be reduced to minimize the risk of internal bleeding.

More specifically, studies investigating the effects of aspirin andrivaroxaban in patients with cardiovascular disease (e.g., coronaryartery disease, carotid artery disease, and acute coronary syndrome)found that low doses of rivaroxaban (2.5 mg BID) and aspirin reduceseveral clinical outcomes, including stroke, myocardial infarction, andcardiovascular death, compared to aspirin alone and a higher dose ofrivaroxaban (5 mg BID) alone. In addition, a 5 mg dose of rivaroxabanalone was also observed to increase the risk of major bleeding eventscompared to aspirin alone. While the combination of 2.5 mg rivaroxaban(BID) and aspirin was also observed to increase the risk of majorbleeding events compared to aspirin alone, the additional clinicalbenefits of this combination therapy outweigh the risks. Thus, in orderto achieve the clinical benefit without causing a dangerous increase inthe internal bleed risk, it is essential to avoid raising the bloodplasma concentration of rivaroxaban to unsafe levels, such as thoseachieved with a 5 mg dose of rivaroxaban alone.

The clinical studies with rivaroxaban and aspirin did not account fordrug-drug interactions with rivaroxaban and moderate CYP3A4 and P-gpinhibitors. This is because the interaction between rivaroxaban and suchmoderate CYP3A4 and P-gp inhibitors was considered to be safe. However,the inventors have surprisingly discovered a previously unknown, andclinically significant drug-drug interaction with the calcium channelblocker, verapamil, a moderate CYP3A4 and P-gp inhibitor.

Verapamil is commonly administered to patients treated with rivaroxabanto treat atrial fibrillation and hypertension. While the prevailingknowledge in the art was that the concomitant administering ofrivaroxaban and verapamil was safe at the recommended dose ofrivaroxaban (i.e., a dose adjustment of rivaroxaban was not required),the inventors unexpectedly discovered that verapamil significantlyincreases the blood plasma levels of rivaroxaban. More specifically, theinventors discovered that concomitant administration of verapamilapproximately doubles the blood plasma concentration of rivaroxaban,such that, e.g., a 20 mg dose of rivaroxaban in the presence ofverapamil becomes a 40 mg dose of rivaroxaban (FIG. 3).

Accordingly, when patients are treated with aspirin, 2.5 mg ofrivaroxaban, and verapamil, the 2.5 mg dose of rivaroxaban willeffectively become a higher dose, for example 5 mg or more. Because a 5mg dose of rivaroxaban (in combination with aspirin) presents anunacceptable bleed risk to a patient, the 2.5 mg dose of rivaroxaban (topatients concomitantly treated with aspirin, rivaroxaban, and verapamil)must be reduced as described herein (e.g., by about 15-95%, inclusive ofall values and ranges in between) in order to safely treat the patient.

Thus, as discussed herein, the methods of the present disclosure aredirected to treating patients with aspirin, rivaroxaban, and verapamil,and require an adjustment of the rivaroxaban dose relative to therecommended dose in that patient if the patient was not concomitantlyadministered verapamil. Alternatively as discussed herein, the methodsof the present disclosure provide for an adjustment of the rivaroxabandose relative to the recommended dose for an otherwise identical patienttreated with aspirin but not concomitantly administered verapamil. Asused herein, the term an “otherwise identical patient who is notconcomitantly administered verapamil” refers to a patient whose physicalcharacteristics relevant to dosing a combination of drugs (e.g.,rivaroxaban and aspirin) are expected to be substantially the same asthat of the patient being treated with a reduced rivaroxaban doseaccording to the presently disclosed methods except for the concomitantadministration of verapamil. In some embodiments, the otherwiseidentical patient will be of substantially the same age, sex, and bodyweight. In some embodiments, the substantially identical patient willalso have substantially identical renal function and drug metabolism. Insome embodiments, the recommended dose of the otherwise identicalpatient who is not concomitantly administered verapamil is the dose thatwould have been recommended to that same patient, had that patient notbeen concomitantly administered verapamil. In particular embodiments,the “recommended dose” of rivaroxaban of the otherwise identical patientwho is not concomitantly administered verapamil (but who is treated withaspirin) is 2.5 mg of rivaroxaban. In further particular embodiments,the otherwise identical patient who is not concomitantly administeredverapamil (but who is treated with aspirin) is administered 2.5 mg orrivaroxaban BID.

In some embodiments, the present disclosure is directed to treatment ofa patient with a medical condition requiring treatment with aspirin (inconjunction with verapamil and a Factor Xa inhibitor), where the purposeof treatment is selected from the group consisting of decreasing therisk of major cardiovascular events (death, myocardial infarction, orstroke) in patients with chronic coronary and/or peripheral arterydisease, reducing the risk of acute limb ischemia in patients withperipheral artery disease, decreasing the risk of major cardiovascularevents (death, myocardial infarction, or stroke) in patients with acutecoronary syndrome, prevention and treatment of venous thromboembolism(also referred to as cancer-associated venous thromboembolism) in cancerpatients or patients with active cancer. Patients treated in this mannercan have normal renal function, or can be mildly, moderately, orseverely renally impaired.

In some embodiments, the present disclosure is directed to methods oftreating a patient in need of antiplatelet and anticoagulant therapieswith aspirin concomitantly with rivaroxaban and verapamil. Daily aspirintherapy is used to reduce platelet aggregation in patients withcardiovascular diseases or at risk of developing cardiovasculardiseases, such as atherosclerosis, patients that have experienced aheart attack or stroke, or have a high risk of a heart attack or stroke,patients with a stent placed in a coronary artery, patients who have hadcoronary bypass surgery, or have chest pain due to coronary arterydisease (e.g., angina), and patients (males over 50 and females olderthan 60) with diabetes and at least one other heart disease risk factor,such as smoking or high blood pressure.

Atrial fibrillation (AF) is a common cardiac disorder that ischaracterized by a disruption of the normal electrical impulsesgenerated by the sinoatrial (SA) node. The resulting disorganizedelectrical impulses lead to an irregular heartbeat and abnormal bloodflow.

AF is also a significant stroke risk factor. The characteristic lack ofcoordinated atrial contraction in AF can result in clot formation in theatrium, and particularly the left atrial appendage of the heart. Theincreased stasis of blood in the atrium due to loss of mechanicalfunction (i.e. contraction), combined with poorly understood changes inthe thrombogenicity of the atrial endocardial surface in AF is thoughtto be the primary basis for clot formation in the left atrium and leftatrial appendage in AF.

If the blood clot leaves the atria and becomes lodged in an artery inthe brain, a stroke results. Diagnosed AF is associated with a four- tofive-fold increase in stroke risk. Approximately 15% of strokes in theU.S. occur in individuals previously diagnosed with AF. It is believedthat even more strokes are associated with undiagnosed AF.

Hypertension is another common cardiac disorder. Hypertension is acondition in which there is an increase in resistance to blood flowthrough the vascular system. This resistance leads to increases insystolic and/or diastolic blood pressures. Hypertension places increasedtension to the left ventricular myocardium, causing it to stiffen andhypertrophy, and accelerates the development of atherosclerosis in thecoronary arteries. The combination of increased demand and lessenedsupply increases the likelihood of myocardial ischemia leading tomyocardial infarction, sudden death, arrhythmias, and congestive heartfailure.

Patients diagnosed with AF and/or hypertension often receive dualtreatment of calcium channel blockers (e.g., for their heart arrhythmiaand/or to lower blood pressure) and anticoagulants to reduce the risk ofstroke.

Rivaroxaban (Formula I), which is commercially available under the tradename Xarelto®, is disclosed in U.S. Pat. No. 7,157,456 (B2), U.S. Pat.No. 7,585,860 (B2), and U.S. Pat. No. 7,592,339 (B2), each of which ishereby incorporated in their entireties for all purposes.

Rivaroxaban is a Factor Xa inhibitor drug used to treatthrombosis-related disorders, among other conditions as disclosedherein. Rivaroxaban activity is mediated though its inhibition of FactorXa, which in turn reduces the conversion of prothrombin to thrombin. Itis also used to help prevent strokes or serious blood clots in peoplewho have atrial fibrillation.

In some embodiments, the present disclosure is directed to methods oftreating a patient in need of treatment with a Factor Xa inhibitor suchas rivaroxaban, concomitantly with aspirin and verapamil. In someembodiments, a non-limiting list of the medical conditions which requiretreatment with a Factor Xa inhibitor (e.g., rivaroxaban) include: atrialfibrillation; deep vein thrombosis; patients undergoing major orthopedicsurgery; deep vein thrombosis prophylaxis, deep vein thrombosisprophylaxis after abdominal surgery; deep vein thrombosis prophylaxisafter hip replacement surgery; deep vein thrombosis prophylaxis afterknee replacement surgery; deep vein thrombosis recurring event; heartattack; prevention of thromboembolism in atrial fibrillation; pulmonaryembolism; pulmonary embolism recurring event; thromboembolic strokeprophylaxis; venous thromboembolism; prevention of ischemic stroke;recurring myocardial infarction; antiphospholipid antibody syndrome;sickle cell disease; prevention and treatment of venous thromboembolismin cancer patients; cancer associated thrombosis; cancer patients withcentral line associated clots in the upper extremity; reducingpost-discharge venous thromboembolism risk in medically ill patients;treating young children with venous thrombosis (6 months 5 years);treatment of arterial or venous thrombosis in children from birth toless than 6 months; thromboprophylaxis in pediatric patients 2 to 8years of age after the fontan procedure; valvular heart disease andatrial fibrillation; patients with atrial fibrillation withbioprosthetic mitral valves; treatment of symptomatic isolated distaldeep vein thrombosis; superficial vein thrombosis; prevention ofthrombosis after replacement of the aortic valve with a biological valveprosthesis; prevention of recurrence of stent thrombosis andcardiovascular events in patients with atrial fibrillation complicatedwith stable coronary artery disease; treatment of splanchnic veinthrombosis; prevention of recurrent thrombosis in patients with chronicportal vein thrombosis; prevention of recurrent symptomatic venousthromboembolism in patients with symptomatic deep vein thrombosis orpulmonary embolism; acute ischemic stroke with atrial fibrillation;venous thromboembolism prophylaxis in patients undergoing non-majororthopedic surgery; reducing the risk of major thrombotic vascularevents in subjects with peripheral artery disease undergoing peripheralrevascularization procedures of the lower extremities; prevention ofcardiovascular events in patients with nonvalvular atrial fibrillationscheduled for cardioversion; reducing the risk of death, myocardialinfarction, or stroke in participants with heart failure and coronaryartery disease following an episode of decompensated heart failure;preventing major cardiovascular events in coronary or peripheral arterydisease; reducing the risk of cardiovascular death, myocardialinfarction, or stroke in patients with recent acute coronary syndrome;prevention of the composite of stroke or systemic embolism in patientswith rheumatic valvular heart disease (RVHD) with atrial fibrillation orflutter who are unsuitable for vitamin K antagonist therapy, or inpatients with RVHD without AF or Flutter with at least one of thefollowing: Left atrial enlargement ≥5.5 cm, Left atrial spontaneous echocontrast, left atrial thrombus, frequent ectopic atrial activity(>1000/24 hours) on Holter ECG; prevention of restenosis afterinfrainguinal percutaneous transluminal angioplasty for critical limbischemia; and decreasing the risk of cardiovascular disease, myocardialinfarction, revascularization, ischemic stroke, and systemic embolism,treatment of arterial or venous thrombosis in neonates, treatment ofvenous thrombosis in young children, aged 6 months to 5 years,prevention of symptomatic venous thromboembolism (VTE) events andVTE-related death post-hospital discharge in high-risk, medically illpatients, reducing the risk of symptomatic lower extremity proximal deepvein thrombosis (DVT), asymptomatic lower extremity proximal DVT,symptomatic upper extremity DVT, symptomatic non-fatal pulmonaryembolism (PE), incidental PE, and venous thromboembolism (VTE)-relateddeath in ambulatory adult participants with various cancer typesreceiving systemic cancer therapy who are at high risk of developing aVTE, treatment of left atrial/left atrial appendage thrombus in subjectswith nonvalvular atrial fibrillation or atrial flutter,thromboprophylaxis in pediatric participants 2 to 8 years of age afterthe Fontan Procedure, reducing the risk of major thrombotic vascularevents in subjects with symptomatic peripheral artery disease undergoingperipheral revascularization procedures of the lower extremities,reducing the risk of death or thromboembolic events after transcatheteraortic valve replacement, prevention of stroke and noncentral nervoussystem systemic embolism in treatment-naïve Asian patients withnon-valvular atrial fibrillation, secondary prevention of stroke andprevention of systemic embolism in patients with a recent embolic strokeof undetermined source, treatment of symptomatic leg superficial veinthrombosis, prophylaxis of VTE in non-major orthopedic surgery,prevention of leaflet thickening and reduced leaflet motion as evaluatedby four-dimensional, volume-rendered computed tomography (4DCT), andprevention of ischemic stroke and neurocognitive impairment in AFreduction in the incidence of clinically significant hematoma aftercontinued or interrupted novel oral anti-coagulant at the time of devicesurgery in patients with moderate to high risk of arterialthromboembolic events. In still other embodiments, the present inventionis directed to treating a condition for which a factor Xa inhibitor isindicated, including reducing the risk of stroke and systemic embolismin patients with non valvular atrial fibrillation, treating deep veinthrombosis (DVT), treating pulmonary embolism (PE), reducing the risk ofDVT, and reducing the risk of PE, the prophylaxis of DVT which leads toPE in patients undergoing knee or hip replacement therapy.

Use of rivaroxaban however, presents risks related to improper dosing.The FDA Draft Guidance on Rivaroxaban (Recommended September 2015)states that rivaroxaban demonstrates a “steep exposure-responserelationship for both efficacy and safety” and therefore should “referto the guidance on warfarin sodium.” In other words, rivaroxaban isrecognized as a drug having a narrow therapeutic index (e.g., meetingnearly all if not all the proposed FDA definitional terms of a NarrowTherapeutic Index drug; [Quality and Bioequivalence Standards for NarrowTherapeutic Index Drugs, Lawrence X Yu, Office of Generic Drugs, GPhA2011 Fall Technical Workshop]), such that higher than expected plasmaconcentrations of rivaroxaban can cause serious adverse events,including internal bleeding/hemorrhage, and underdosing leaves a patientat risk of potentially fatal clotting events. Careful monitoring ofpatients treated with rivaroxaban is made even more difficult by thecurrent lack of commercially available, specific antidotes againstrivaroxaban overdosing, the lack of specific treatments with provenefficacy for severe bleeding linked with the use of rivaroxaban, and thelack of a routine coagulation test suitable for monitoring patientstreated with rivaroxaban (as discussed herein). Conventional methods forreducing plasma levels which are useful for other anticoagulants such asdabigatran (e.g. haemodialysis and FDA-approved specific antidoteidarucizumab) are not effective for rivaroxaban, because rivaroxabancannot be eliminated from the body through dialysis and idarucizumabdoes not work against rivaroxaban.

The risks associated with incorrectly dosing rivaroxaban have caused thedrug to be placed on the Institute for Safe Medication Practices (ISMP)list of high-alert medications as a drug with “heightened risk ofcausing significant potential harm.” (Institute for Safe MedicationPractices (ISMP) “ISMP List of High-Alert Medications in Acute CareSettings” https://www.ismp.org/tools/highalertmedications.pdf (AccessedOctober 2015)).

As provided in the rivaroxaban package insert (as revised October 2017for NDA 022406 and 6/27/18 for NDA 202439), the 15 mg and 20 mg tabletsshould be taken with food, and the 10 mg tablets taken with or withoutfood. For patients with nonvalvular atrial fibrillation, with CL_(Cr)>50mL/min (normal to mild renal impairment), the 20 mg dose with theevening meal is recommended. For such patients with CL_(Cr) 15-50 mL/min(severe to moderate renal impairment), the 15 mg dose with the eveningmeal is recommended. For patients with DVT, PE it is recommended thatpatients be administered 15 mg twice daily with food for the first 21days, then 20 mg once daily with food for the remaining treatment. Forthe prophylaxis of DVT following hip or knee replacement surgery, 10 mgonce daily is recommended with or without food. To reduce the risk ofrecurrence of DVT and/or PE in patients at continued risk for DVT and/orPE, it is recommended that patients be administered 10 mg once dailywith or without food, after at least 6 months of standard anticoagulanttreatment.

With respect to drug-drug interactions, the rivaroxaban package insertrecommends avoiding concomitant use of rivaroxaban with combined P-gpand strong CYP3A4 inhibitors and inducers—that is, rivaroxaban and thecombined P-gp and strong CYP3A4 inhibitors or inducers should not becoadministered; rather, one or the other drug should be discontinued.Although concomitant administration of rivaroxaban with drugs such aserythromycin, which is considered in the Xarelto® package insert to be acombined P-gp and moderate CYP3A4 inhibitor, has been observed toincrease exposure to rivaroxaban, the package insert indicates that noprecautions are necessary in such coadministration if the change inexposure is not expected to affect bleeding risk (see section 7.1 of thepackage insert), but that otherwise rivaroxaban should not be usedunless the potential benefit justifies potential risk (see section 7.5of the package insert). However, various studies discussed herein haveshown that there are as yet no suitable assays for monitoringrivaroxaban dosing or assessing potential risk. (see e.g., Favarolo etal., Biochemia Medica 2012; 22(3): 329-41; Xarelto® Package Insert).

Thus, although drug-drug interactions with rivaroxaban are known (e.g.,elevated exposure to rivaroxaban in the presence of combined P-gp andCYP3A4 inhibitors), only in the case of coadministration of rivaroxabanand combined P-gp and strong CYP3A4 inhibitors is it necessary to changethe dosing, e.g., by eliminating (i.e., avoiding) the use ofrivaroxaban. Indeed, until the inventors' discovery, those of skill inthe art have not identified clinically relevant interactions betweenrivaroxaban and commonly prescribed medications by virtue ofrivaroxaban's multiple elimination pathways. (See W. Mueck et al., ClinPharmacokinet (2014) 53:1-16). Thus, to-date, studies of drug-druginteractions with rivaroxaban have only identified that thecoadministration of rivaroxaban with combined P-gp and strong CYP3A4inhibitors (or strong inducers) is clinically relevant and thusrequiring any modification of rivaroxaban dosing. In such instances itis recommended that the rivaroxaban (or alternatively the stronginhibitor/inducer) be eliminated entirely from the treatment. Prior tothe inventors' discovery, a dose reduction of rivaroxaban has not beenrecommended to address a clinically relevant drug-drug interaction.

In some embodiments, rivaroxaban dosing is compared in terms of itspharmacokinetic responses in different patients or patient populations,and in response to different situations. For example, in someembodiments, the present disclosure teaches methods of adjustingrivaroxaban dosing in patients concomitantly administered rivaroxaban,aspirin, and verapamil, relative to otherwise identical (or the same)patients not concomitantly administered aspirin and verapamil, in orderto provide a particular rivaroxaban AUC_(inf), AUC_(ss), C_(max),C_(max ss) or C_(ave) (or a range of values of such parameters) in saidpatient or patient population.

In other embodiments, rivaroxaban dosing is compared in terms of itspharmacokinetic and pharmacodynamics effects. For example, in someembodiments, the present disclosure teaches methods of adjustingrivaroxaban dosing in patients concomitantly administered rivaroxaban,aspirin, and verapamil, relative to otherwise identical (or the same)patients not concomitantly administered verapamil, in order to provide aparticular prothrombin time or decrease the incidence rate of adverseevents (or range of values of such parameters) in said patient orpatient population.

Rivaroxaban pharmacokinetics and pharmacodynamics are at least partiallya consequence of the drug's excretion/secretion and metabolism,particularly when coadministered with verapamil. Approximately one-third(36%) of each rivaroxaban dose is eliminated in the patient's urine asunprocessed active drug. Of this 36% elimination, 30% is eliminatedthrough active renal secretion, while the remaining 6% is eliminatedthough glomerular filtration.

Renal impairment can also have effects on the pharmacodynamics ofrivaroxaban. Even moderate changes in rivaroxaban AUC and half-life(t_(1/2)) can lead to significant changes in haemostasis. In subjectswith mild, moderate, and severe renal impairment administered a 10 mgdose of rivaroxaban, the AUEC for Factor Xa inhibition was 1.5-fold,1.86-fold, and 2.0-fold higher than in healthy subjects, respectively.(Kubitza et al. Effects of renal impairment on the pharmacokinetic,pharmacodynamics and safety of rivaroxaban, an oral, direct Factor Xainhibitor. Brit J of Clinical Pharma 70:5 703-712). In this work Kubitzaet al. did not evaluate patients administered 2.5 or 5 mg doses, orevaluate drug-drug interactions. However, even in such studies, Kubitzaet al. found that such increases in rivaroxaban exposure were unlikelyto be clinically relevant, and that safety profiles were similar inpatients with differing levels of renal impairment. Thus, Kubitza et al.did not recognize any need to adjust rivaroxaban doses in such patients.

However, the inventors have found that the recommended rivaroxaban doseshould be adjusted in patients who are coadministered aspirin andverapamil. Thus in some embodiments, the present disclosure is directedto methods of treating patients comprising adjusting rivaroxaban dosingin response to changes in a patient's renal function.

Renal secretion of rivaroxaban is partially regulated by thePermeability glycoprotein (P-gp) pathway. P-gp transporters are found inthe luminal membrane of several tissues, including the blood-brainbarrier, the small intestine excretory cells, hepatocytes, and kidneyproximal tubule epithelia. P-gp expression on intestinal epithelialcells regulates cellular uptake and absorption of drugs intoenterocytes, whereas expression of P-gp transporters on the surface ofhepatocytes and renal tubular cells regulates the elimination of drugsinto the bile and urine.

In some embodiments, the present disclosure teaches that P-gp inductionor inhibition can result in different pharmacokinetic andpharmacodynamic responses to fixed rivaroxaban doses. For example, insome embodiments, the present disclosure teaches that P-gp inhibitioncan lead to rivaroxaban overdosing due to decreased renal excretion ofthe drug.

P-gp inhibition is thought to involve modulation by 1 of 4 pathways:direct inhibition of binding sites that block the transport ofsubstrates, ATP binding inhibition, ATP hydrolysis, or coupling of ATPhydrolysis to the translocation of the substrate.

Unfortunately, molecules that are modulators of P-gp substrates do notshare any obvious structural characteristics, and it is thus difficultto predict the effect of concomitant administration of a drug on P-gpfunction.

Moreover, different drugs may interact differentially with P-gp, whichresults in a distinct mechanism of modulation of P-gp activity. As shownby Polli et al., Journal of Pharmacology and Experimental Therapeutics,vol. 299(2), 620-628 (2001), various assays of P-gp inhibition can givewidely varying results. Polli et al. describe three different P-gpassays: the monolayer efflux assay (using Caco-2 cells), the ATPase andcalcein-AM assays. Of the three, the monolayer efflux assay isconsidered the most reliable because it is a direct measurement ofefflux. Polli et al. demonstrated that verapamil does not show efflux(i.e., is not a P-gp substrate) in the monolayer efflux assay, butprovides positive results in the ATPase and calcein-AM assays.

Gnoth et al., Journal of Pharmacology and Experimental Therapeutics,vol. 338(1), 372-380 (2011) evaluated the P-gp transport characteristicsof rivaroxaban, and rivaroxaban in the presence of potential P-gpinhibitors such as clarithromycin and erythromycin. The authors observedthat erythromycin did not inhibit P-gp-mediated efflux of rivaroxabanacross cell monolayers in vitro—in fact, erythromycin increased theefflux of rivaroxaban in a statistically significant manner. Thus,erythromycin and verapamil utilize distinct mechanisms in theirinteraction with and regulation of P-gp activity, which could lead todiffering inhibitory effects. Gnoth et al. concluded that the impact ofP-gp inhibition, alone, had only a marginal effect on thepharmacokinetics of rivaroxaban, and that only strong P-gp inhibitors athigh doses might result in drug-drug interactions.

Approximately two-thirds of each rivaroxaban dose is subject tometabolic degradation via the liver's oxidative and hydrolytic pathways.

At least three functional CYP3A proteins exist in humans. The CYP3A4monooxygenase is the predominant cytochrome P450 in human liver andsmall bowel. The protein displays a broad substrate specificity and itmetabolizes more than 60% of all drugs that are currently in use,including contraceptive steroids, antidepressants, benzodiazepines,immunosuppressive agents, imidazole antimicotics, and macrolideantibiotics.

Rivaroxaban metabolic clearance is catalyzed by CYP3A4/5, CYP2J2, andCYP-independent mechanisms. The CYP3A4 isozyme in particular, accountsfor approximately 18% of the rivaroxaban clearance.

In some embodiments, the present disclosure teaches that variations inCYP3A4 activity can result in different pharmacokinetic andpharmacodynamic responses to fixed rivaroxaban doses. A considerablevariation in the CYP3A4 content and catalytic activity has beendescribed in the general population. For example, studies have shownthat the metabolic clearance of the CYP3A4 substrates exhibit a unimodaldistribution with up to 20-fold variability between individual patients.This result is also born out in direct activity studies whichdemonstrated that the activities of the CYP3A4 protein in liver biopsiesvary up to 30-fold between individuals.

In order to assess the effects of combined P-gp and CYP3A4 inhibitors onthe metabolism of rivaroxaban, a study was conducted to examine theeffects of co-administration of rivaroxaban with erythromycin, acombined moderate CYP3A4 inhibitor and P-gp inhibitor. Erythromycin isknown to be eliminated mainly in the bile, and 2-15% renally(unchanged). However, based on this study, no dose adjustment forrivaroxaban in the presence of such a combined inhibitor was found to benecessary. Similar results were obtained for clarithromycin andfluconazole, suggesting significant interactions with other drugs inthis category are unlikely. (Mueck et al. Co-administration ofrivaroxaban with drugs that share its elimination pathways:pharmacokinetic effects in healthy subjects. British J. of ClinicalPharma 76:3 455-466).

On the contrary, the FDA-approved rivaroxaban label states thatrivaroxaban use should be avoided (i.e., should not be administered atall) in patients receiving “concomitant combined P-gp and moderateCYP3A4 inhibitors” unless “the potential benefit justifies the potentialrisk.” However, since, as discussed herein there is no clinicallystandardized test methodology for evaluating the pharmacodynamics ofrivaroxaban as there are for other, conventional anticoagulants such aswarfarin and heparin (i.e., PT/INR or APTT tests), there is noclinically acceptable or useful methodology for evaluating the potentialrisk.

In some embodiments, the present disclosure is directed to methods ofadjusting rivaroxaban doses in response to CYP3A4 induction orinhibition. In some embodiments, the present invention thus teaches thatthe concomitant administration of other drugs can alter CYP3A4expression levels (via induction or repression). For example, some knowninducers of CYP3A4 expression include drugs such as the glucocorticoiddexamethasone, the antibiotic rifampicin, and the antimycoticclotrimazole. Like the regulation of P-gp secretion however, the effectof any drug on CYP3A4 activity is difficult to predict.

In addition to metabolism by CYP3A4, 14% of rivaroxaban is metabolizedby CYP2J2. It has been shown that verapamil can inhibit greater than 95%of metabolism by CYP2J2 in vitro, while erythromycin did not demonstratesignificant inhibition of CYP2J2 activity. The clinical implications ofthe potential inhibition of CYP2J2-mediated metabolism of rivaroxaban byverapamil are as yet unknown.

Thus in some embodiments, the present disclosure is directed to methodsof treating patients in need of Factor Xa inhibitor treatment, saidmethod comprising adjusting rivaroxaban dosing (as described herein) inresponse to changes in a patient's altered liver drug metabolism.

Verapamil is a calcium channel blocker used in the treatment of angina,arrhythmia, and essential hypertension among other uses, for example asdisclosed herein. Verapamil is extensively metabolized to a number ofmetabolites, at least one of which (norverapamil) retains significantactivity and is itself a P-gp inhibitor. Approximately 70% is excretedin the urine (mainly as metabolites, but about 4% unchanged), andapproximately 16% in the feces.

Verapamil is a popular drug, used daily by millions of older patientswith heart issues. The prevalent use of the drug has caused it to belisted in the World Health Organizations (WHO) list of essentialmedicines (found athttp://www.who.int/medicines/publications/essentialmedicines/en/).

In some embodiments, the present disclosure is directed to treatment ofa patient with a medical condition requiring treatment with a calciumchannel blocker such as verapamil (in conjunction with a Factor Xainhibitor), including management of essential hypertension, treatment ofhypertension, treatment of pulmonary hypertension, prevention andtreatment of recurrent and paroxysmal supraventricular tachycardia,management of supraventricular tachycardia, treatment of atrialtachycardia and junctional tachycardia, treatment of cerebral vasospasm,treatment of hypertrophic cardiomyopathy, treatment of chronic stableangina pectoris, treatment of unstable angina pectoris, management ofPrinzmetal variant angina, ventricular rate control in atrialfibrillation/flutter, prevention of cluster headache, prevention ofmigraine, prevention of myocardial infarction in patients with preservedleft ventricular function, management of manic manifestations of bipolardisorder, treatment of Raynaud's disease, treatment of coronary arterydisease, treatment of subarachnoid hemorrhage, treatment of DravetSyndrome, beta cell survival therapy in Type I diabetes, treatment ofvestibular migraine, treatment of chronic subjective dizziness,treatment of erectile dysfunction, prevention of keloid recurrence,treatment of refractory epilepsy, treatment of refractory meningioma,treatment of chronic heart failure secondary to non-ischemiccardiomyopathy, treatment of relapsed or refractory Hodgkin lymphoma,treatment of Marfan Syndrome, treatment of treatment-resistant mania,prevention of kidney disease in diabetic patients, treatment ofMetabolic Syndrome, and treatment of hypoglycemia following gastricbypass.

In particular, verapamil has become an effective treatment for atrialfibrillation and hypertension. Verapamil has been shown to prolong theeffective refractory period within the atrioventricular (AV) node toslow AV conduction in a dose-dependent manner. This property accountsfor the ability of verapamil to slow the ventricular rate in patientswith chronic atrial flutter or atrial fibrillation, reducing thesubjective sensation of palpitations. Verapamil has also been shown torelax the tone of the smooth muscle lining blood vessels and dilate theblood vessels. This property, among others, attributes to verapamil'sutility as an antihypertensive agent. Typical daily doses of verapamilfor such patients range from about 40 mg to about 480 mg, often dividedin 3 to 4 equal doses during the day. Alternatively, extended releaseverapamil formulations can be administered once a day, in daily doses of100 mg to 400 mg, (including 40 mg, 100 mg, 200 mg, 300 mg, and 400 mg).Verapamil is available in various dosage forms including withoutlimitation extended-release capsules (100, 120, 180, 200, 240, 300, and360 mg), extended-release tablets (120, 180, and 240 mg), immediaterelease tablets (40, 80, and 120 mg doses), IV solutions (5 mg/2 mL and10 mg/4 mL), and as combination formulations (e.g., extended releasetrandolapril/verapamil HCl tablets, 1 mg/240 mg, 2 mg/180 mg, 2 mg/240mg, 4 mg/240 mg). In some embodiments, when verapamil is administered asan extended-release capsule or an extended-release tablet, it isadministered 1 or 2 times daily. In some embodiments, when verapamil isadministered as an immediate-release tablet, it is administered 3 or 4times daily.

Thus patients with atrial fibrillation are often prescribed verapamil totreat heart palpitations, and rivaroxaban to reduce the risk of stroke.

The present disclosure is at least partially based on the inventors'discovery that the concomitant administration of verapamil andrivaroxaban leads to an unexpectedly increased risk of rivaroxabanoverdosing and adverse drug effects. Consequently, as a result of theincreased rivaroxaban levels, patients concomitantly administeredrivaroxaban, aspirin, and verapamil are at a significantly greater riskfor major bleeding events. Without wishing to be bound by any onetheory, the present inventors believe that administration of verapamiland rivaroxaban leads to an unexpected clinically significant drug-druginteraction that negatively impacts the metabolic and excretionclearance of rivaroxaban and can lead to increased adverse events, suchas a major bleeding event. Because such patients are also being treatedwith aspirin, and the concomitant administration with rivaroxabanalready presents a bleed risk to the patients, the dosing regimen mustbe appropriately adjusted for patients on verapamil. Thus, in at leastsome embodiments, the present invention is a method of reducing the sideeffects (increased bleeding, such as gastrointestinal orgastrointestinal bleeding) when verapamil and aspirin are coadministeredwith rivaroxaban, by adjusting the rivaroxaban dose to less than thecurrently recommended dose as described herein. In alternativeembodiments, the present invention is a method of reducing the sideeffects (increased bleeding, such as gastrointestinal or intracranialbleeding) when verapamil and aspirin are coadministered withrivaroxaban, by administering a formulation which releases rivaroxabansuch that the pharmacokinetic profile of rivaroxaban is similar (e.g.,bioequivalent) to that of an identical patient not treated withverapamil and who is administered 2.5 mg rivaroxaban BID. In someembodiments, the rivaroxaban formulation can be an extended releaseformulation, an immediate release formulation, or a formulationcomprising an instant release component and a delayed or extendedrelease component.

For example, in certain embodiments, the rivaroxaban dose for a patientconcomitantly administered rivaroxaban, aspirin, and verapamil is in therange of about 0.5 mg to less than about 2.5 mg, e.g., about 0.5 mg,about 0.75 mg, about 1.0 mg, about 1.25 mg, about 1.5 mg, about 1.75 mg,about 2.0 mg, and about 2.25 mg, inclusive of all values and subrangestherebetween. In some such embodiments, the recommended rivaroxaban dosefor a patient concomitantly administered rivaroxaban, aspirin, andverapamil is about 1.75 mg. In some other particular embodiments, suchas when at least a portion of the dose of rivaroxaban is administered ina delayed release or extended release formulation, the rivaroxaban dosefor a patient concomitantly administered rivaroxaban, aspirin, andverapamil is in the range of from about 0.5 mg to less than about 5 mg,e.g., about 0.5 mg, about 0.75 mg, about 1.0 mg, about 1.25 mg, about1.5 mg, about 1.75 mg, about 2.0 mg, about 2.25 mg, about 2.5 mg, about2.75 mg, about 3.0 mg, about 3.25 mg, about 3.5 mg, about 3.75 mg, about4.0 mg, about 4.25 mg, about 4.5 mg, and about 4.75 mg, inclusive of allvalues and subranges therebetween.

Likewise, for any of the adjusted rivaroxaban doses enumerated above,the daily aspirin dose ranges from about 25 mg to about 400 mg, or about75 mg to about 400 mg. In some embodiments, the aspirin is administeredin multiple doses (e.g., from 2-12 daily doses). In some embodiments,the aspirin is administered once daily (e.g., a single 100 mg dose). Forexample the daily aspirin dose may be about 25, about 30, about 35,about 40, about 45, about 50, about 60, about 70, about 75, about 80,about 90, about 100, about 125, about 150, about 175, about 200, about225, about 250, about 275, about 300, about 325, about 350, about 375,about 400 mg, about 450, about 500, about 550, about 600, about 650,about 700, about 750, about 800, about 850, about 900, about 950, about1000, about 1050, about 1100, about 1150, about 1200, about 1250, about1300, about 1350, about 1400, about 1450, about 1500, about 1550, about1600, about 1650, about 1700, about 1750, about 1800, about 1850, about1900, about 1950, about 2000, about 2050, about 2100, about 2150, about2200, about 2250, about 2300, about 2350, about 2400, about 2450, about2500, about 2550, about 2600, about 2650, about 2700, about 2750, about2800, about 2850, about 2900, about 2950, about 3000, about 3050, about3100, about 3150, about 3200, about 3250, about 3300, about 350, about3400, about 3450, about 3500, about 3550, about 3600, about 3650, about3700, about 3750, about 3800, about 3850, about 3900, about 3950, andabout 4000 mg.

Likewise, for any of the adjusted rivaroxaban doses enumerated above,the daily verapamil dose ranges from about 100 mg to about 480 mg perday (e.g., about 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg,170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg,260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg,350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg,440 mg, 450 mg, 460 mg, 470 mg or about 480 mg), whether administered asa divided dose (e.g., 2-4 times daily) or a single extended releasedose.

Verapamil is classified as an inhibitor of cytochrome P450 CYP3A4 andalso as an inhibitor of the transporter permeability-glycoprotein(P-gp). Verapamil has been classified by the FDA as a moderate inhibitorof CYP3A4, but has less of an inhibitory effect on excretion ofedoxaban, a similar Factor Xa inhibitor, than erythromycin, which isalso viewed by the FDA as a moderate CYP3A4 inhibitor. Furthermore,erythromycin and verapamil are metabolized (cleared) from the body of apatient in substantially different ways. Erythromycin is mainlymetabolized by demethylation in the liver by the CYP3A4 enzyme, and iseliminated primarily in the bile, with little renal excretion (2-15%unchanged drug). In contrast, as discussed above, verapamil undergoesextensive hepatic metabolism, and its metabolites are excreted primarilyin the urine. Additionally, some metabolites (i.e., norverapamil andmetabolite D-703) also have inhibitory potential toward P-gp(Pauli-Magnus C et al. “Characterization of the Major Metabolites ofVerapamil as Substrates and Inhibitors of P-glycoprotein.” J PharmacolExp Ther 2000; 293:376-382). The clinical relevance of inhibition ofP-gp by the metabolites of verapamil is as yet unknown. Thus, verapamiland erythromycin are quite different in their respective metaboliccharacteristics, particularly renal clearance and the mechanisms bywhich they interact with P-gp, and thus studies ofrivaroxaban/erythromycin co-administration would not be expected toprovide clinical insights directly relevant to any drug-druginteractions between rivaroxaban and verapamil.

In some embodiments, the present disclosure teaches that the concomitantadministration of verapamil leads to a reduction in the body's clearance(metabolism and excretion) of rivaroxaban. Moreover, atrial fibrillationis a disease associated with older patients, with a median age of about70 years old, who may have age-related renal impairment. Thus in someembodiments, the present disclosure teaches that reduced rivaroxabanclearance due to concomitant administration of verapamil is also likelyexacerbated by age-related impairment and/or renal impairment ofpatients receiving the drug.

Because of the drug-drug interaction between verapamil and rivaroxaban,the present disclosure teaches, in some embodiments, that theconcomitant administration of verapamil with aspirin and rivaroxaban isassociated with higher proportion of adverse events (such as majorbleeding events), for example compared to otherwise identical (or thesame) patient populations in which verapamil is not administered.

In some embodiments, the present disclosure teaches that rivaroxabanpharmacokinetics are at least partially affected by changes in apatient's CYP3A4 metabolism and P-gp secretion. The present disclosuredemonstrates however, that general knowledge about the secretion andmetabolism pathways of rivaroxaban are not sufficiently clear to predictwhether any particular drug would have undesirable drug interaction(s)with rivaroxaban, or that such undesirable interaction(s) could beaddressed effectively by the specific dose adjustments of rivaroxabanprovided herein, rather than, e.g., eliminating one or both drugs fromthe patient's treatment. Indeed, the general knowledge in the artindicates that, except for strong combined CYP3A4/P-gp inhibitors, anynoted change in rivaroxaban exposure is not clinically relevant, andcoadministration of rivaroxaban and strong combined CYP3A4/P-gpinhibitors is to be avoided entirely.

This document has already described that P-gp inhibitors do not shareany obvious structural characteristics that could be used to predict adrug's effect on P-gp secretion. Similarly (despite many structuralmodeling efforts), the molecular structure of a drug is not dispositiveof a drug's effect on CYP3A4 inhibition. It would therefore bedifficult, if not impossible, for a person having ordinary skill in theart to predict a drug's effect on liver metabolism or renal secretionsolely based on its structure.

Moreover, as discussed below, in some embodiments, the present inventionalso teaches that even empirical evidence of a drug's inhibition ofCYP3A4 metabolism and/or P-gp secretion, is still not predictive ofwhether the drug will have a clinically relevant effect on rivaroxabanexposure.

Previous studies have demonstrated that concomitant administration ofother CYP3A4 and P-gp inhibitors did not produce clinically relevanteffects on rivaroxaban exposure or the prevalence of adverse events. Forexample, other studies have shown that concomitant administration ofrivaroxaban and erythromycin (a moderate CYP3A4 and strong P-gpinhibitor) produced a 34% rivaroxaban exposure increase. Similarly,concomitant administration of rivaroxaban with clarithromycin (anotherstrong CYP3A4 inhibitor and moderate P-gp inhibitor) produced a 54%rivaroxaban exposure increase. The concomitant administration ofrivaroxaban and fluconazole (a moderate CYP3A4 inhibitor) produced a 42%rivaroxaban exposure increase. Thus the present disclosure teaches thatnot all CYP3A4 and P-gp inhibitors exhibit clinically relevant drug-druginteractions with rivaroxaban.

Verapamil and erythromycin are also dosed quite differently.Erythromycin is an antibiotic useful for the treatment of variousbacterial infections, and is usually administered for relatively shortperiods of time, e.g. 1-2 weeks. In contrast, verapamil is typicallyadministered to treat chronic conditions such as hypertension, anginapectoris, cardiac arrhythmias, etc. and is administered over much longerperiods of time. These conditions for which verapamil is administeredare common comorbidities and indications that would also requiretreatment with rivaroxaban.

The present inventors observed that patients concomitantly administeredverapamil and rivaroxaban represented 30% of the reported rivaroxabanserious bleeding adverse events, despite accounting for only 22% of thetotal population receiving rivaroxaban. This was unexpected in view ofthe teachings of the prior art which suggested no clinically relevantdrug-drug interactions existed between verapamil and rivaroxaban. Forexample, Xarelto's® (rivaroxaban) own product insert concludes thatconcomitant use of rivaroxaban with verapamil did not result inincreased patient bleeding (see ROCKET AF trial in section 7.5 ofXarelto® product insert (revised August 2016). Additionally, a posterpresented on Nov. 8, 2015 at the American Heart Association 2015Scientific Sessions concluded that use of non-dihydropyridine calciumchannel blockers such as verapamil with rivaroxaban was not associatedwith an increased risk of non-major clinically relevant or majorbleeding compared to subjects on non-dihydropyridine calcium channelblockers and warfarin (see Poster S4081 Efficacy and Safety ofRivaroxaban versus Warfarin in Patients Taking Non-dihydropyridineCalcium Channel Blockers: Results from the ROCKET-AF Trial, presentedNov. 8, 2015, American Heart Association, Scientific Sessions 2015, andpublished athttp://www.abstractsonline.com/pp8/#!/3795/presentation/37668).

Moreover, the present disclosure also teaches that the increasedincidence of adverse events was not common to all CYPA34 and P-gpinhibitors, but was rather unexpectedly specific to verapamil. Forexample, in some embodiments, the present disclosure teaches thatconcomitant administration of rivaroxaban and erythromycin (anothermoderate CYP3A4 inhibitor and strong P-gp inhibitor) is not associatedwith increased serious bleeding adverse events.

The present invention's discovery of the need to adjust the dose ofrivaroxaban when coadministered with aspirin and verapamil was alsounexpected based on, among other factors, the lack of any perceivedclinically relevant drug-drug interactions between rivaroxaban andsubstrates of CYP enzymes (e.g., Mueck et al.), the expected weaker P-gpinhibition of verapamil compared to erythromycin, verapamil's previoushistory of safe concomitant administration with other anticoagulants,including other direct Factor Xa inhibitors. For example, previousstudies reviewing the interaction between edoxaban (an oral directFactor Xa inhibitor) and verapamil, concluded that theirco-administration did not lead to any increased bleeding or otheradverse events (Mendell et al., Drug-drug interaction studies ofcardiovascular drugs involving p-glycoprotein, an efflux transporter, onthe pharmacokinetics of edoxaban, an oral Factor Xa inhibitor. Am. J.Cardiovasc Drugs (2013) 13:331-342). Accordingly, the label for SAVAYSA™(edoxaban) does not suggest reduced dosing for patients concomitantlyadministered with verapamil (SAVAYSA™ product insert, Highlights ofprescribing information (revised September 2016), found athttp://dsi.com/prescribing-information-portlet/getPIContent?productName=Savaysa).Moreover, the SAVAYSA™ product insert shows that concomitantadministration of edoxaban and verapamil has a smaller impact onedoxaban exposure compared to concomitant administration edoxaban witherythromycin, as shown by the lower GMR values for the C_(max) and AUCparameters of verapamil compared to erythromycin (e.g., Figure 12.1 ofthe SAVAYSA™ product insert). Thus, to the extent edoxaban/verapamilcoadministration may be predictive of the drug-drug interactionsexpected for coadministered rivaroxaban/verapamil, the effects ofverapamil coadministration would be expected to be appreciably less thanfor erythromycin coadministration. However, the SAVAYSA™ product insertdoes not recommend dose adjustment of edoxaban when coadministered witheither erythromycin or verapamil.

Similarly, the only clinically significant drug-drug interactionsidentified in the ELIQUIS® (apixaban) package insert (revised September2015) are with strong dual CYP3A4 and P-gp inhibitors such asketoconazole, itraconazole, and, and clarithromycin.

In addition, the dabigatran (PRADAXA®) label, another anticoagulant,states that interaction of dabigatran with various P-gp inhibitors(e.g., verapamil, amiodarone, quinidine, clarithromycin and ticagrelor)does not require a dose adjustment of PRADAXA®, and that this conclusionshould not be extrapolated to other P-gp inhibitors, further indicatingthat P-gp inhibition is unpredictable and one of skill in the art wouldnot use the study of a particular drug to directly inform dosinginstructions for another drug. For this reason, studies of interactionsbetween, for example, rivaroxaban and erythromycin is not a goodpredictor for interactions between e.g. rivaroxaban and verapamil.

Lastly, the betrixaban (BEVYXXA®) label, a recently approvedanticoagulant, states that concomitant use of P-gp inhibitors, such asverapamil, results in increased exposure to betrixaban, and patientsshould reduce the dose of betrixaban (Section 7.1; revised June 2017).However, the respective labels indicate that rivaroxaban and betrixabanare treated quite differently clinically in the context of drug-druginteractions. More specifically, the betrixaban label recommends thatpatients concomitantly treated with ketoconazole should reduce the doseof betrixaban by 50%, whereas the rivaroxaban label contraindicatescoadministration with ketoconazole. For patients concomitantly treatedwith clarithromycin, the betrixaban label recommends reducing the doseof betrixaban by 50%, whereas there is no clinically relevant drug-druginteraction reported for rivaroxaban and thus the full dose ofrivaroxaban is administered. For patients concomitantly treated withcarbamazepine, the betrixaban label does not report a clinicallyrelevant drug-drug interaction and the full dose of betrixaban can beadministered, whereas the rivaroxaban label contraindicatescoadministration. Thus, the drug-drug interactions expected forcoadministered rivaroxaban/verapamil would be expected to be entirelydifferent than for betrixaban/verapamil.

In addition, to the extent that the Xarelto® (rivaroxaban) PackageInsert indicates that concomitant use of combined P-gp and CYP3A4inhibitors is contraindicated or should be avoided (due to reducedelimination of rivaroxaban), there are a number of known alternativeanticoagulants, such as apixaban, edoxaban, or dabigatran, better safetyand/or efficacy profiles in patients with reduced clearance. See forexample Nielsen et al., Clin. Res. Cardiol. 22 Nov. 2014 (publishedonline) which refers to apixaban as a first line choice for patientswith impaired renal elimination due to its comparable efficacy andfavorable safety profile.

The current FDA approved dosing scheme for rivaroxaban includes aonce-daily 10-20 mg dose. Specifically, patients with nonvalvular atrialfibrillation, deep vein thrombosis, or pulmonary embolism, arerecommended to take a once-daily 20 mg oral dose with the evening meal,while patients with deep vein thrombosis following hip or kneereplacement surgery are recommended to take a once-daily 10 mg dose withor without food. Xarelto's® (rivaroxaban) product insert does notcurrently recommend a dose reduction with verapamil(https://www.xareltohep.com/shared/product/xarelto/prescribing-information.pdf).In addition, clinical trials are investigating a dosing scheme of 2.5 mgof rivaroxaban in combination with a low dose aspirin to reduce the riskof cardiovascular events. Notably, however, these clinical trials havenot investigated the impact of moderate CYP3A4 and P-gp inhibitors onthe risk of major bleeding events because, prior to the Applicant'sdiscovery, rivaroxaban was considered to have no clinically relevantdrug-drug interaction with such moderate CYP3A4 and P-gp inhibitors.

In some embodiments, the present disclosure provides a method oftreating a patient with rivaroxaban, comprising (a) administering about100 to about 480 mg of verapamil daily to the patient; (b) administeringabout 75 mg to about 325 mg of aspirin to the patient; and (c)administering about 0.5 mg to about 2.5 mg of rivaroxaban to thepatient. As described herein, the claimed range of rivaroxaban iscritical to safely and effectively treat a disorder (e.g., a clottingdisorder) while minimizing the patient's risk of a major bleeding event.

In some embodiments, the dose of verapamil administered in step (a) is120, 240, 360, or 480 mg. For example, in some embodiments, the dose ofverapamil administered in step (a) is 120 mg. In some embodiments, thedose of verapamil administered in step (a) is 240 mg. In someembodiments, the dose of verapamil administered in step (a) is 360 mg.In some embodiments, the dose of verapamil administered in step (a) is480 mg.

In some embodiments, the dose of aspirin administered in step (b) is 75,81, 100, 125, 150, 175, 200, 225, 250, 275, 300, or 325 mg. For example,in some embodiments, the dose of aspirin administered in step (b) is 100mg.

In some embodiments, the dose of rivaroxaban administered in step (c) isabout 0.5 mg to less than 2.5 mg of rivaroxaban. In some embodiments,the dose of rivaroxaban is administered in an immediate release or rapidrelease formulation. In some embodiments, the dose of rivaroxabanadministered in step (c) ranges from about 0% to about 95% of the doserecommended for an otherwise identical patient who is not concomitantlyadministered and verapamil. In some embodiments, the dose of rivaroxabanadministered in step (c) ranges from about 0.5 mg to about 2.0 mg (forexample about 0.5 mg, about 0.75 mg, about 1.0 mg, about 1.25 mg, about1.5 mg, about 1.75 mg, and about 2.0 mg).

In some embodiments, the patient is administered the dose of rivaroxabantwice daily (BID). In some embodiments, the total daily dose ofrivaroxaban administered to the patient is less than 5 mg (e.g., thetotal daily dose of rivaroxaban administered to the patient is about 0.5mg, about 0.75 mg, about 1.0 mg, about 1.25 mg, about 1.5 mg, about 1.75mg, about 2.0 mg, about 2.25 mg, about 2.5 mg, about 2.75 mg, about 3.0mg, about 3.25 mg, about 3.5 mg, about 3.75 mg, about 4.0 mg, about 4.25mg, about 4.5 mg, or about 4.75 mg).

Thus in some embodiments, the present disclosure is directed to theadministration of a reduced rivaroxaban dose, in which the reducedrivaroxaban dose is between about 0%-99.5% of the recommended dose foran otherwise identical (or the same) patient who is not concomitantlyadministered aspirin and verapamil, e.g., 0%, about 1%, about 2%, about3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%,about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%,about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%,about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%,about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%,about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%,about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%,about 95%, about 96%, about 97%, about 98%, 99%, or 99.5%, including allranges therebetween.

In some embodiments, the patient is administered from about 0.5 mg toless than about 5 mg of rivaroxaban once daily, wherein at least aportion of the dose of rivaroxaban is administered in a delayed releaseor extended release component. In some embodiments, rivaroxaban isreleased at a rate such that the pharmacokinetic profile of rivaroxabanis similar (e.g., bioequivalent) to that of an identical patient nottreated with verapamil who is administered 2.5 mg rivaroxaban BID. Insome embodiments, the extended release or delayed release formulationcomprises an immediate release component which has about 2.0 mg or lessof rivaroxaban (e.g., from 0.5-2.0 mg, including 1.75 mg) and providesblood plasma levels of rivaroxaban that are similar (e.g.,bioequivalent) to an otherwise identical patient treated with a singledose of 2.5 mg of rivaroxaban but who is not concomitantly administeredverapamil. In some embodiments, after the blood plasma levels ofrivaroxaban decrease, the extended release or delayed release componentprovides blood plasma levels of rivaroxaban that are similar (e.g.,bioequivalent) to an otherwise identical patient treated with 2.5 mg ofrivaroxaban BID but who is not concomitantly administered verapamil. Theextended release or delayed release component can be appropriatelyformulated to account for residual blood plasma concentrations ofrivaroxaban from the immediate release component so as to achieve safeblood plasma levels of rivaroxaban (e.g., less than those correspondingto 5 mg of rivaroxaban in an otherwise identical patient treated who isnot concomitantly administered verapamil). In other embodiments, theextended release formulation releases rivaroxaban at a rate such thatthe pharmacokinetic profile of rivaroxaban is similar (e.g.,bioequivalent) to that of an identical patient not treated withverapamil who is administered 2.5 mg rivaroxaban BID.

In some embodiments, the present disclosure is directed to a method oftreating a patient in need of a Factor Xa inhibitor, said methodcomprising the step of administering one or more reduced rivaroxabandose(s) (relative to the recommended dose for an otherwise identical (orthe same) patient treated with aspirin but not concomitantlyadministered verapamil as described herein) of about 10 μg/Kg, 20 μg/Kg,30 μg/Kg, 40 μg/Kg, 50 μg/Kg, 60 μg/Kg, 70 μg/Kg, 80 μg/Kg, 90 μg/Kg,100 μg/Kg, 110 μg/Kg, 120 μg/Kg, 130 μg/Kg, 140 μg/Kg, 150 μg/Kg, 160μg/Kg, 170 μg/Kg, 180 μg/Kg, 190 μg/Kg, 200 μg/Kg, 210 μg/Kg, 220 μg/Kg,230 μg/Kg, 240 μg/Kg, 250 μg/Kg, 260 μg/Kg, 270 μg/Kg, 280 μg/Kg, 290μg/Kg, 300 μg/Kg, 310 μg/Kg, 320 μg/Kg, 330 μg/Kg, 340 μg/Kg, 350 μg/Kg,360 μg/Kg, 370 μg/Kg, 380 μg/Kg, 390 μg/Kg, 400 μg of rivaroxaban perKilogram of body weight.

Thus in some embodiments, the present disclosure is directed to theadministration of a reduced rivaroxaban dose, in which the reducedrivaroxaban dose (relative to the recommended dose for an otherwiseidentical (or the same) patient treated with aspirin but notconcomitantly administered verapamil as described herein) is betweenabout 10 μg/kg-300 μg/kg of body weight, inclusive of all ranges andsubranges therebetween. For example, in some embodiments, the presentdisclosure is directed to the administration of a reduced rivaroxabandose (relative to the recommended dose for an otherwise identical (orthe same) treated with aspirin but not concomitantly administeredverapamil as described herein), in which the reduced rivaroxaban dose isreduced to between about 100 μg/kg-150 μg/kg of body weight.

In various embodiments, the present disclosure is directed to a methodof treating a patient with a reduced dose of rivaroxaban relative to therecommended dose of rivaroxaban for an otherwise identical (or the same)patient treated with aspirin but not concomitantly administeredverapamil. Persons having skill in the art will readily recognize thatthat a clinically effective dose of rivaroxaban for a patient may bedependent on various factors including patient age, sex, body weight,disease progression, overall heath, pathological state, tolerance to thedrug, dosing frequency, route of administration, etc. However, the“recommended dose” is the dose recommended in the art as suitable for aparticular patient or patient population based on recognized, clinicallyrelevant physical criteria as established during e.g. clinical trialsupon which FDA approval is based. Thus in some embodiments, the presentdisclosure teaches that an “otherwise identical” patient who is notconcomitantly administered verapamil is a patient that has substantiallyidentical physical and biophysical characteristics as the treatedpatient, other than the administration of verapamil. Thus in someembodiments, an identical patient could be an experimental controlpatient in studies evaluating the reduced rivaroxaban dosing treatmentsof the present disclosure. In some embodiments, the recommended dose is2.5 mg of rivaroxaban administered twice daily (BID).

In the methods of the present disclosure, the rivaroxaban can beadministered by any suitable method or mode. For example the compound ofthe formula (I) can be administered in various forms as describedherein, e.g., capsules, tablets, oral solutions or suspensions, drypowders, or parenteral dosage forms such as injectable or IV solutionsor suspensions.

Dosing Regimens

In some embodiments, the present disclosure is directed to methods oftreating a patient in need of treatment with a Factor Xa inhibitor andwho is concomitantly administered aspirin and verapamil, wherein saidmethod comprises administering more than one dose of rivaroxaban perday. Thus in some embodiments the present disclosure is directed tomethods of administering, 1, 2, or 3 doses of rivaroxaban per day. Insome embodiments, the present disclosure is directed to administering 2daily doses of rivaroxaban with food. In various of these embodiments,said multiple doses are reduced doses according to the presentdisclosure. In some embodiments, the patient is administered the dose ofrivaroxaban twice daily. In some embodiments, the total daily dose ofrivaroxaban administered to the patient is less than 5 mg. In someembodiments, the total daily dose of rivaroxaban administered to thepatient is about 0.5 mg, about 0.75 mg, about 1.0 mg, about 1.25 mg,about 1.5 mg, about 1.75 mg, about 2.0 mg, about 2.25 mg, about 2.5 mg,about 2.75 mg, about 3.0 mg, about 3.25 mg, about 3.5 mg, about 3.75 mg,about 4.0 mg, about 4.25 mg, about 4.5 mg, or about 4.75 mg.

The present disclosure contemplates a variety of dosing regimens. Forexample, the present disclosure encompasses all combinations of dosingrivaroxaban (e.g., 1 or 2 or more times daily), verapamil (i.e., 1, 2,3, or 4 or more times daily), and aspirin (i.e., 1, 2, 3, 4, 5, 6, 7, 8,9, or 10 or more times daily). Typical daily doses of verapamil for suchpatients range from about 40 mg to about 480 mg, often divided in 3 to 4equal doses during the day. Alternatively, extended release verapamilformulations can be administered once a day, in daily doses of 100 mg to400 mg, (including 40 mg, 100 mg, 200 mg, 300 mg, and 400 mg). Verapamilis available in various dosage forms including without limitationextended-release capsules (100, 120, 180, 200, 240, 300, and 360 mg),extended-release tablets (120, 180, and 240 mg), immediate releasetablets (40, 80, and 120 mg doses), IV solutions (5 mg/2 mL and 10 mg/4mL), and as combination formulations (e.g., extended releasetrandolapril/verapamil HCl tablets, 1 mg/240 mg, 2 mg/180 mg, 2 mg/240mg, 4 mg/240 mg).

Thus, in some embodiments, verapamil is administered to a patient oncedaily at any dose (e.g., 100, 120, 180, 200, 240, 300, or 360 mg).Accordingly, in some embodiments, when verapamil is administered to apatient once daily, rivaroxaban may be administered once daily andaspirin may be administered once daily. In some embodiments, whenverapamil is administered to a patient once daily, rivaroxaban may beadministered twice daily and aspirin may be administered once daily.

In some embodiments, verapamil is administered to a patient twice dailyat any dose (e.g., 100, 120, 180, 200, or 240 mg in an extended releaseformulation). Accordingly, in some embodiments, when verapamil isadministered to a patient twice daily, rivaroxaban may be administeredonce daily and aspirin may be administered once daily. In someembodiments, when verapamil is administered to a patient twice daily,rivaroxaban may be administered twice daily and aspirin may beadministered once daily.

In some embodiments, verapamil is administered to a patient three timesdaily (e.g., 100 or 120 mg in an extended release formulation).Accordingly, in some embodiments, when verapamil is administered to apatient three times daily, rivaroxaban may be administered once dailyand aspirin may be administered once daily. In some embodiments, whenverapamil is administered to a patient three times daily, rivaroxabanmay be administered twice daily and aspirin may be administered oncedaily.

In some embodiments, verapamil is administered to a patient four timesdaily (e.g., 100 or 120 mg in an extended release formulation).Accordingly, in some embodiments, when verapamil is administered to apatient four times daily, rivaroxaban may be administered once daily andaspirin may be administered once daily. In some embodiments, whenverapamil is administered to a patient four times daily, rivaroxaban maybe administered twice daily and aspirin may be administered once daily.

In some embodiments, the present disclosure is directed to treating apatient in need of treatment with rivaroxaban and aspirin, wherein thepatient is not concomitantly administered verapamil (i.e., thecoadministration of rivaroxaban and verapamil is contraindicated forsuch patients). That is, in some embodiments disclosed herein, thepatient administered rivaroxaban in combination with aspirin, orverapamil in combination with aspirin, but not both rivaroxaban andverapamil. In some embodiments, the present methods are directed totreating a patient in need of treatment with rivaroxaban and who isconcomitantly administered aspirin and verapamil, wherein the patientceases verapamil and then is administered rivaroxaban. In alternativeembodiments, the patient is currently being treated with rivaroxaban andaspirin but is need of treatment with verapamil; the patient ceasestreatment with rivaroxaban and then is administered verapamil. Invarious embodiments, the patient has normal renal function, or in otherembodiments, the patient has renal insufficiency (mild, moderate orsevere as described herein)

Thus, in some embodiments, the patient is administered rivaroxaban incombination with aspirin, but not verapamil. In other embodiments, thepatient is administered verapamil in combination with aspirin, but notrivaroxaban. In accordance with these embodiments, in order totransition a patient treated with verapamil to rivaroxaban, a patient adelay period of about 1-21 days between ceasing administration ofverapamil and starting administration of the rivaroxaban is required inorder to avoid or reduce the incidence of side effects resulting fromadministration of the verapamil. For example, the delay period may beabout 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,20, or 21 days. After the delay period, rivaroxaban may be administeredas described herein or at the reference dose. In some embodiments, thepatient is mildly renally impaired. In some embodiments, the patient ismoderately renally impaired. In some embodiments, the patient isseverely renally impaired. In accordance with any of these embodiments,after the washout period, the patient may take a reduced dose ofverapamil. After the delay period, rivaroxaban is administered asdescribed herein or at the reference dose. In accordance with any ofthese embodiments, after the delay period, the patient may take areduced dose of rivaroxaban. For example, the reduced rivaroxaban doseis about 0%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%,about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%,about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%,about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%,about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%,about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%,about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%,about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%,about 98%, 99%, or 99.5% of the rivaroxaban dose recommended for anotherwise identical (or the same) patient who is not concomitantlyadministered aspirin and verapamil, including all ranges therebetween.

Pharmacokinetic and Pharmacodynamic Characteristics

As discussed above, in various embodiments, the disclosure provides formethods of treating a patient with an immediate or rapid releaseformulation comprising from about 0.5 mg to less than about 2.5 mg ofrivaroxaban. In some embodiments, the present disclosure provides amethod of treating a patient with rivaroxaban, wherein afteradministering the dose of rivaroxaban, the patient has at least one ofthe following characteristics: (i) a geometric mean of an area under theplasma concentration-time curve (AUC) of rivaroxaban in the range offrom about 80% of about 165.4 μg·h/L to about 125% of about 551.9 μg·h/Lafter a single dose of rivaroxaban in the range of from about 0.5 mg toless than about 2.5 mg; (ii) a geometric mean of a maximum blood plasmaconcentration (C_(max)) of rivaroxaban in the range of from about 80% of28.6 μg/L to about 125% of 103.0 μg/L after a single dose of rivaroxabanin the range of from about 0.5 mg to less than about 2.5 mg; (iii) arisk of major bleeding of no more than about 4.5%; or (iv) a prothrombintime of 20-30 seconds. For example, in some embodiments, afteradministering the dose of rivaroxaban, the patient has one of theaforementioned characteristics. In some embodiments, after administeringthe dose of rivaroxaban, the patient has two of the aforementionedcharacteristics. In some embodiments, after administering the dose ofrivaroxaban, the patient has three of the aforementionedcharacteristics. In some embodiments, after administering the dose ofrivaroxaban, the patient has four of the aforementioned characteristics.

In some embodiments, the present disclosure provides a method oftreating a patient with an immediate or rapid release formulationcomprising from about 0.5 mg to less than about 2.5 mg of rivaroxaban,wherein after administering the dose of rivaroxaban, the patient has atleast one of the following characteristics: (i) a geometric mean AUC ofrivaroxaban that is less than 1064.25 μg·h/L after a single dose ofrivaroxaban in the range of from about 0.5 mg to less than about 2.5 mg;and (ii) a geometric mean C_(max) of rivaroxaban that is less than181.25 μg/L after a single dose of rivaroxaban in the range of fromabout 0.5 mg to less than about 2.5 mg; (iii) a risk of major bleedingof no more than about 4.5%; or (iv) a prothrombin time of 20-30 seconds.For example, in some embodiments, after administering the dose ofrivaroxaban, the patient has one of the aforementioned characteristics.In some embodiments, after administering the dose of rivaroxaban, thepatient has two of the aforementioned characteristics. In someembodiments, after administering the dose of rivaroxaban, the patienthas three of the aforementioned characteristics. In some embodiments,after administering the dose of rivaroxaban, the patient has four of theaforementioned characteristics.

In some embodiments, the patient who is administered a reduced amount ofthe recommended dose of rivaroxaban, as described herein, experiencesthe same or lower C_(max) of rivaroxaban compared to the otherwiseidentical (or the same) patient who is administered the recommended doseof rivaroxaban and aspirin but is not concomitantly administeredverapamil. Thus, in some embodiments, the present disclosure is directedto administering a reduced rivaroxaban dose (relative to the recommendeddose for an otherwise identical (or the same) patient treated withaspirin but not concomitantly administered verapamil as describedherein), wherein the rivaroxaban C_(max) (including the C_(max) measuredafter a single dose and steady state C_(max), C_(max ss)) of saidpatient for the inventive dosing regimen is less than about 200 μg/L,about 195 μg/L, about 190 μg/L, about 185 μg/L, about 180 μg/L, about175 μg/L, about 170 μg/L, about 165 μg/L, about 160 μg/L, about 158μg/L, about 155 μg/L, about 150 μg/L, about 145 μg/L, about 140 μg/L,about 135 μg/L, about 130 μg/L, about 125 μg/L, about 120 μg/L, about115 μg/L, about 110 μg/L, about 105 μg/L, about 100 μg/L, about 95 μg/L,about 90 μg/L, about 85 μg/L, about 80 μg/L, about 75 μg/L, about 70μg/L, about 65 μg/L, about 60 μg/L, about 55 μg/L, about 50 μg/L, about45 μg/L, about 40 μg/L, about 35 μg/L, about 30 μg/L, about 25 μg/L, andabout 20 μg/L, inclusive of all ranges and subranges therebetween.

In some embodiments, the present disclosure is directed to theadministration of a reduced rivaroxaban dose (relative to therecommended dose for an otherwise identical (or the same) patienttreated with aspirin but not concomitantly administered verapamil asdescribed herein), in which the reduced rivaroxaban dose produces arivaroxaban C_(max) (including C_(max) measured after a single dose andsteady state C_(max), C_(max ss)) between about from about 80% of 28.6μg/L to about 125% of 103.0 μg/L, e.g., about 20 μg/L, about 25 μg/L,about 30 μg/L, about 35 μg/L, about 40 μg/L, about 45 μg/L, about 50μg/L, about 55 μg/L, about 60 μg/L, about 65 μg/L, about 70 μg/L, about75 μg/L, about 80 μg/L, about 85 μg/L, about 90 μg/L, about 95 μg/L,about 100 μg/L, about 105 μg/L, about 110 μg/L, about 115 μg/L, about120 μg/L, about 125 μg/L, and about 130 μg/L, inclusive of all valuesand subranges therebetween.

In some embodiments, the reduced rivaroxaban dose provides the same orlower AUC of rivaroxaban compared to an otherwise identical (or thesame) patient who is receiving the recommended rivaroxaban dose andaspirin but is not concomitantly administered verapamil. Thus, in someembodiments, the present disclosure is directed to the administration ofa reduced rivaroxaban dose (relative to the recommended dose for anotherwise identical (or the same) patient not concomitantly administeredverapamil as described herein), wherein the rivaroxaban AUC (include AUCmeasured after a single dose, and AUC_(inf) or AUC_(ss)) of said patientis lower than about 150 (μg/L)·h, about 175 (μg/L)·h, about 200(μg/L)·h, about 225 (μg/L)·h, about 250 (μg/L)·h, about 275 (μg/L)·h,about 300 (μg/L)·h, about 325 (μg/L)·h, about 350 (μg/L)·h, about 375(μg/L)·h, about 400 (μg/L)·h, about 425 (μg/L)·h, about 450 (μg/L)·h,about 475 (μg/L)·h, about 500 (μg/L)·h, about 525 (μg/L)·h, about 550(μg/L)·h, about 575 (μg/L)·h, about 600 (μg/L)·h, about 625 (μg/L)·h,650 (μg/L)·h, about 675 (μg/L)·h, about 700 (μg/L)·h, about 725(μg/L)·h, about 750 (μg/L)·h, about 775 (μg/L)·h, about 800 (μg/L)·h,about 825 (μg/L)·h, about 850 (μg/L)·h, about 875 (μg/L)·h, about 900(μg/L)·h, about 925 (μg/L)·h, about 950 (μg/L)·h, about 975 (μg/L)·h,about 1000 (μg/L)·h, about 1025 (μg/L)·h, about 1050 (μg/L)·h, or about1064.25 (μg/L)·h, inclusive of all ranges and subranges there between.

Thus in some embodiments, the present disclosure is directed to theadministration of a reduced rivaroxaban dose (relative to therecommended dose for an otherwise identical (or the same) patienttreated with aspirin but not concomitantly administered verapamil asdescribed herein), in which the reduced rivaroxaban dose provides an AUCbetween about 80% of about 165.4 μg·h/L to about 125% of about 551.9μg·h/L after a single dose of rivaroxaban, e.g., 150 (μg/L)·h, about 175(μg/L)·h, about 200 (μg/L)·h, about 225 (μg/L)·h, about 250 (μg/L)·h,about 275 (μg/L)·h, about 300 (μg/L)·h, about 325 (μg/L)·h, about 350(μg/L)·h, about 375 (μg/L)·h, about 400 (μg/L)·h, about 425 (μg/L)·h,about 450 (μg/L)·h, about 475 (μg/L)·h, about 500 (μg/L)·h, about 525(μg/L)·h, about 550 (μg/L)·h, about 575 (μg/L)·h, about 600 (μg/L)·h,about 625 (μg/L)·h, about 650 (μg/L)·h, about 675 (μg/L)·h, and about700 (μg/L)·h, inclusive of all ranges and subranges therebetween.

In some embodiments, the present disclosure is directed to methods ofreducing the rivaroxaban dose of patients who are concomitantlyadministered aspirin and verapamil (relative to the recommended dose foran otherwise identical (or the same) patient treated with aspirin butnot concomitantly administered verapamil as described herein), whereinthe reduced dose causes the patient to maintain the approximately thesame maximum prothrombin time compared to an otherwise identical (or thesame) patient who is not concomitantly administered verapamil and isreceiving the recommended dose of rivaroxaban. Thus in some embodiments,the present disclosure is directed to a reduced rivaroxaban dose(relative to the recommended dose for an otherwise identical (or thesame) patient treated with aspirin but not concomitantly administeredverapamil as described herein), wherein the patient's maximumprothrombin time is lower than about 20s, 21s, 22s, 23s, 24s, 25s, 26s,27s, 28s, 29s, or about 30s.

In some embodiments, the present disclosure is directed to methods ofreducing the rivaroxaban dose of patients who are concomitantlyadministered aspirin and verapamil (relative to the recommended dose foran otherwise identical (or the same) patient treated with aspirin butnot concomitantly administered verapamil as described herein), whereinthe reduced dose of rivaroxaban provides a % risk of major bleeding, forexample using the relation shown in FIG. 5, which is less than about12%, less than about 11%, less than about 10%, less than about 9%, lessthan about 8%, less than about 7%, less than about 6%, less than about5%, less than about 4.5%, less than about 4%, less than about 3.5%, lessthan about 3%, less than about 2.5%, less than about 2%, less than about1.5%, or less than about 1%. In some embodiments, the patient's risk ofa major bleeding event is less than about 5%. In still otherembodiments, said patients hereinabove may have normal renal function,or mild, moderate, or severe renal impairment.

In some embodiments, the present disclosure is directed to methods ofreducing the rivaroxaban dose of patients with mild renal impairmentrelative to the recommended dose for an otherwise identical patienthaving normal renal function, wherein the reduced dose of rivaroxabanprovides a % risk of major bleeding, for example using the relationshown in FIG. 5, which is less than about 12%, less than about 11%, lessthan about 10%, less than about 9%, less than about 8%, less than about7%, less than about 6%, less than about 5%, less than about 4.5%, lessthan about 4%, less than about 3.5%, less than about 3%, less than about2.5%, less than about 2%, less than about 1.5%, or less than about 1%.In some embodiments, the patient's risk of a major bleeding event isless than about 5%.

As discussed above, in various embodiments, the disclosure provides formethods of treating a patient, once daily, with a delayed or extendedrelease component comprising from about 1.75 mg to less than about 5.0mg of rivaroxaban. In some such embodiments, the present disclosureprovides a method of treating a patient with rivaroxaban, wherein afteradministering the dose of rivaroxaban, the patient has at least one ofthe following characteristics: (i) a geometric mean of an area under theplasma concentration-time curve (AUC) of rivaroxaban that is within therange of about 80%-125% of the AUC measured for an otherwise identicalpatient that was administered 2.5 mg of rivaroxaban, BID, but was notadministered verapamil; (ii) a geometric mean of a maximum blood plasmaconcentration (Cmax) of rivaroxaban in the range of from about 80% of28.6 μg/L to about 125% of 103.0 μg/L; (iii) a risk of major bleeding ofno more than about 4.5%; or (iv) a prothrombin time of 20-30 seconds.For example, in some embodiments, after administering the dose ofrivaroxaban, the patient has one of the aforementioned characteristics.In some embodiments, after administering the dose of rivaroxaban, thepatient has two of the aforementioned characteristics. In someembodiments, after administering the dose of rivaroxaban, the patienthas three of the aforementioned characteristics. In some embodiments,after administering the dose of rivaroxaban, the patient has four of theaforementioned characteristics.

In some embodiments, the present disclosure provides a method oftreating a patient, once daily, with a delayed or extended releaseformulation comprising from about 2.5 mg to less than about 5.0 mg ofrivaroxaban, wherein after administering the dose of rivaroxaban, thepatient has at least one of the following characteristics: (i) ageometric mean of an area under the plasma concentration-time curve(AUC) of rivaroxaban that is less than the AUC measured for an otherwiseidentical patient that was administered 5.0 mg of rivaroxaban, twicedaily, but was not administered verapamil; and (ii) a geometric meanC_(max) of rivaroxaban that is less than 181.25 μg/L; (iii) a risk ofmajor bleeding of no more than about 4.5%; or (iv) a prothrombin time of20-30 seconds. For example, in some embodiments, after administering thedose of rivaroxaban, the patient has one of the aforementionedcharacteristics. In some embodiments, after administering the dose ofrivaroxaban, the patient has two of the aforementioned characteristics.In some embodiments, after administering the dose of rivaroxaban, thepatient has three of the aforementioned characteristics. In someembodiments, after administering the dose of rivaroxaban, the patienthas four of the aforementioned characteristics.

In some embodiments, the patient experiences a C_(max) of rivaroxabanthat is the same or lower than the C_(max) of an otherwise identical (orthe same) patient who is administered the recommended dose ofrivaroxaban and aspirin but is not concomitantly administered verapamil.Thus, in some embodiments, the rivaroxaban C_(max) (including theC_(max) measured after a single dose and steady state C_(max),C_(max ss)) of said patient is less than about 200 μg/L, about 195 μg/L,about 190 μg/L, about 185 μg/L, about 180 μg/L, about 175 μg/L, about170 μg/L, about 165 μg/L, about 160 μg/L, about 158 μg/L, about 155μg/L, about 150 μg/L, about 145 μg/L, about 140 μg/L, about 135 μg/L,about 130 μg/L, about 125 μg/L, about 120 μg/L, about 115 μg/L, about110 μg/L, about 105 μg/L, about 100 μg/L, about 95 μg/L, about 90 μg/L,about 85 μg/L, about 80 μg/L, about 75 μg/L, about 70 μg/L, about 65μg/L, about 60 μg/L, about 55 μg/L, about 50 μg/L, about 45 μg/L, about40 μg/L, about 35 μg/L, about 30 μg/L, about 25 μg/L, and about 20 μg/L,inclusive of all ranges and subranges therebetween.

In some embodiments, the C_(max) (including C_(max) measured after asingle dose and steady state C_(max), C_(max ss)) is between about fromabout 80% of 28.6 μg/L to about 125% of 103.0 μg/L, e.g., about 20 μg/L,about 25 μg/L, about 30 μg/L, about 35 μg/L, about 40 μg/L, about 45μg/L, about 50 μg/L, about 55 μg/L, about 60 μg/L, about 65 μg/L, about70 μg/L, about 75 μg/L, about 80 μg/L, about 85 μg/L, about 90 μg/L,about 95 μg/L, about 100 μg/L, about 105 μg/L, about 110 μg/L, about 115μg/L, about 120 μg/L, about 125 μg/L, and about 130 μg/L, inclusive ofall values and subranges therebetween.

In some embodiments, the dose of rivaroxaban in the extended or delayedrelease formulation provides the same or lower AUC of rivaroxabancompared to an otherwise identical (or the same) patient who isreceiving the recommended rivaroxaban dose and aspirin but is notconcomitantly administered verapamil. Thus, in some embodiments, apatient treated according to the present methods will have a geometricmean of an area under the plasma concentration-time curve (AUC) ofrivaroxaban that is within the range of about 80%-125% of the AUCmeasured for an otherwise identical patient that was administered 2.5 mgof rivaroxaban, BID, but was not administered verapamil i.e., within therange of 80% of 330.8 to 125% of 1103.8. In some embodiments, therivaroxaban AUC (include AUC measured after a single dose, and AUC_(inf)or AUC_(ss)) of said patient is lower than about 150 (μg/L)·h, about 175(μg/L)·h, about 200 (μg/L)·h, about 225 (μg/L)·h, about 250 (μg/L)·h,about 264.64 (m/L)·h, about 275 (μg/L)·h, about 300 (μg/L)·h, about 325(μg/L)·h, about 350 (μg/L)·h, about 375 (μg/L)·h, about 400 (μg/L)·h,about 425 (μg/L)·h, about 450 (μg/L)·h, about 475 (μg/L)·h, about 500(μg/L)·h, about 525 (μg/L)·h, about 550 (μg/L)·h, about 575 (μg/L)·h,about 600 (μg/L)·h, about 625 (μg/L)·h, 650 (μg/L)·h, about 675(μg/L)·h, about 700 (μg/L)·h, about 725 (μg/L)·h, about 750 (μg/L)·h,about 775 (μg/L)·h, about 800 (μg/L)·h, about 825 (μg/L)·h, about 850(μg/L)·h, about 875 (μg/L)·h, about 900 (μg/L)·h, about 925 (μg/L)·h,about 950 (μg/L)·h, about 975 (μg/L)·h, about 1000 (m/L)·h, about 1025(m/L)·h, about 1050 (m/L)·h, about 1064.25 (m/L)·h, about 1075 (μg/L)·h,about 1100 (m/L)·h, about 1125 (m/L)·h, about 1150 (m/L)·h, about 1175(m/L)·h, about 1200 (m/L)·h, about 1225 (m/L)·h, about 1250 (m/L)·h,about 1275 (m/L)·h, about 1300 (m/L)·h, about (μg/L)·h, about 1325(μg/L)·h, about 1350 (μg/L)·h, about 1375 (μg/L)·h, or about 1379.75(μg/L)·h, inclusive of all ranges and subranges there between.

In some embodiments, the patient has an AUC that is less than the AUCmeasured for an otherwise identical patient that was administered 5.0 mgof rivaroxaban, twice daily, but was not administered verapamil, e.g.,less than about 2,759.5 (μg/L)·h, less than about 2,750 (μg/L)·h, lessthan about 2,725 (μg/L)·h, less than about 2,700 (μg/L)·h, less thanabout 2,675 (μg/L)·h, less than about 2,650 (μg/L)·h, less than about2,625 (μg/L)·h, less than about 2,600 (μg/L)·h, less than about 2,575(μg/L)·h, less than about 2,550 (μg/L)·h, less than about 2,525(μg/L)·h, less than about 2,500 (μg/L)·h, less than about 2,475(μg/L)·h, less than about 2,450 (μg/L)·h, less than about 2,425(μg/L)·h, less than about 2,400 (μg/L)·h, less than about 2,375(μg/L)·h, less than about 2,350 (μg/L)·h, less than about 2,325(μg/L)·h, less than about 2,300 (μg/L)·h, less than about 2,275(μg/L)·h, less than about 2,250 (μg/L)·h, less than about 2,225(μg/L)·h, less than about 2,200 (μg/L)·h, less than about 2,175(μg/L)·h, less than about 2,150 (μg/L)·h, less than about 2,125(μg/L)·h, less than about 2,100 (μg/L)·h, less than about 2,075(μg/L)·h, less than about 2,050 (μg/L)·h, less than about 2,025(μg/L)·h, less than about 2,000 (μg/L)·h, less than about 1,975(μg/L)·h, less than about 1,950 (μg/L)·h, less than about 1,925(μg/L)·h, less than about 1,900 (μg/L)·h, less than about 1,875(μg/L)·h, less than about 1,850 (μg/L)·h, less than about 1,825(μg/L)·h, less than about 1,800 (μg/L)·h, less than about 1,775(μg/L)·h, less than about 1,750 (μg/L)·h, less than about 1,725(μg/L)·h, less than about 1,700 (μg/L)·h, less than about 1,675(μg/L)·h, less than about 1,650 (μg/L)·h, less than about 1,625(μg/L)·h, less than about 1,600 (μg/L)·h, less than about 1,575(μg/L)·h, less than about 1,550 (μg/L)·h, less than about 1,525(μg/L)·h, less than about 1,500 (μg/L)·h, less than about 1,475(μg/L)·h, less than about 1,450 (μg/L)·h, less than about 1,425(μg/L)·h, less than about 1,400 (μg/L)·h, less than about 1,375(μg/L)·h, less than about 1,350 (μg/L)·h, less than about 1,325(μg/L)·h, less than about 1,300 (μg/L)·h, less than about 1,275(μg/L)·h, less than about 1,250 (μg/L)·h, less than about 1,225(μg/L)·h, less than about 1,200 (μg/L)·h, less than about 1,175(μg/L)·h, less than about 1,150 (μg/L)·h, less than about 1,125(μg/L)·h, less than about 1,100 (μg/L)·h, less than about 1,075(μg/L)·h, less than about 1,050 (μg/L)·h, less than about 1,025(μg/L)·h, less than about 1,000 (μg/L)·h, less than about 975 (μg/L)·h,less than about 950 (μg/L)·h, less than about 925 (μg/L)·h, less thanabout 900 (μg/L)·h, less than about 875 (μg/L)·h, less than about 850(μg/L)·h, less than about 825 (μg/L)·h, less than about 800 (μg/L)·h,less than about 775 (μg/L)·h, less than about 750 (μg/L)·h, less thanabout 725 (μg/L)·h, less than about 700 (μg/L)·h, less than about 675(μg/L)·h, less than about 650 (μg/L)·h, less than about 625 (μg/L)·h,less than about 600 (μg/L)·h, less than about 575 (μg/L)·h, less thanabout 550 (μg/L)·h, less than about 525 (μg/L)·h, less than about 500(μg/L)·h, less than about 475 (μg/L)·h, less than about 450 (μg/L)·h,less than about 425 (μg/L)·h, or less than about 400 (μg/L)·h.

In some embodiments, the present disclosure is directed to methods ofreducing the rivaroxaban dose of patients who are concomitantlyadministered aspirin and verapamil (relative to the recommended dose foran otherwise identical (or the same) patient treated with aspirin butnot concomitantly administered verapamil as described herein), whereinthe reduced dose causes the patient to maintain the approximately thesame maximum prothrombin time compared to an otherwise identical (or thesame) patient who is not concomitantly administered verapamil and isreceiving the recommended dose of rivaroxaban. Thus in some embodiments,the present disclosure is directed to a reduced rivaroxaban dose(relative to the recommended dose for an otherwise identical (or thesame) patient treated with aspirin but not concomitantly administeredverapamil as described herein), wherein the patient's maximumprothrombin time is lower than about 20s, 21s, 22s, 23s, 24s, 25s, 26s,27s, 28s, 29s, or about 30s.

In some embodiments, the present disclosure is directed to methods ofreducing the rivaroxaban dose of patients who are concomitantlyadministered aspirin and verapamil (relative to the recommended dose foran otherwise identical (or the same) patient treated with aspirin butnot concomitantly administered verapamil as described herein), whereinthe reduced dose of rivaroxaban provides a % risk of major bleeding, forexample using the relation shown in FIG. 5, which is less than about12%, less than about 11%, less than about 10%, less than about 9%, lessthan about 8%, less than about 7%, less than about 6%, less than about5%, less than about 4.5%, less than about 4%, less than about 3.5%, lessthan about 3%, less than about 2.5%, less than about 2%, less than about1.5%, or less than about 1%. In some embodiments, the patient's risk ofa major bleeding event is less than about 5%. In still otherembodiments, said patients hereinabove may have normal renal function,or mild, moderate, or severe renal impairment.

In some embodiments, the present disclosure is directed to methods ofreducing the rivaroxaban dose of patients with mild renal impairmentrelative to the recommended dose for an otherwise identical patienthaving normal renal function, wherein the reduced dose of rivaroxabanprovides a % risk of major bleeding, for example using the relationshown in FIG. 5, which is less than about 12%, less than about 11%, lessthan about 10%, less than about 9%, less than about 8%, less than about7%, less than about 6%, less than about 5%, less than about 4.5%, lessthan about 4%, less than about 3.5%, less than about 3%, less than about2.5%, less than about 2%, less than about 1.5%, or less than about 1%.In some embodiments, the patient's risk of a major bleeding event isless than about 5%.

Thus in some embodiments, the present disclosure is directed to theadministration of a reduced rivaroxaban dose (relative to therecommended dose for an otherwise identical (or the same) patienttreated with aspirin but not concomitantly administered verapamil asdescribed herein), in which the reduced rivaroxaban dose causes saidpatient to exhibit a maximum a prothrombin time between about 20s-30s,inclusive of all ranges and subranges therebetween. For example, in someembodiments, the present disclosure is directed to the administration ofa reduced rivaroxaban dose (relative to the recommended dose for anotherwise identical (or the same) patient treated with aspirin but notconcomitantly administered verapamil as described herein), in which thereduced rivaroxaban dose produces a maximum prothrombin time betweenabout 20s-30s.

Indications

The present disclosure is also directed to a method of treating apatient in need of treatment with a Factor Xa inhibitor, an NSAID (suchas aspirin), and a calcium channel blocker (such as verapamil), whereinthe treatment is to decrease the risk of major cardiovascular events(death, myocardial infarction, or stroke) in patients with chroniccoronary and/or peripheral artery disease; reduce the risk of acute limbischemia in patients with peripheral artery disease; decrease the riskof major cardiovascular events (death, myocardial infarction, or stroke)in patients with acute coronary syndrome; and prevention and treatmentof venous thromboembolism (also referred to as cancer-associated venousthromboembolism) in cancer patients or patients with active cancer. Insome embodiments, the method can include administering a daily dose ofabout 100, 120, 180, 240 300, 360, or about 480 mg verapamil, a dose ofaspirin (e.g., about 75 mg to about 325 mg), and a reduced dose ofrivaroxaban (as described herein). In some embodiments, the patient hasmild, moderate, or severe renal impairment.

The present disclosure is also directed to a method of treating a personin need of a calcium channel blocker comprising administering a dose ofaspirin (e.g., about 75 mg to about 325 mg, e.g., about 100 mg), a doseof verapamil (100, 120, 180, 240 300, 360, or about 480 mg), and a doseof rivaroxaban which is less than the dose recommended for an otherwiseidentical (or the same) patient who is not concomitantly administeredverapamil. In some embodiments, the calcium channel blocker indicatedfor the treatment of essential hypertension or atrial fibrillation. Insome embodiments, the method can include administering a daily dose ofabout 100, 120, 180, 240, about 360, or about 480 mg of verapamil,including all ranges and subranges therebetween to the patient,administering a dose of aspirin (e.g., about 75 mg to about 325 mg) andadministering a dose of rivaroxaban as described herein. In someembodiments, the patient can have mild, moderate, or severe renalimpairment and is in need of anticoagulant therapy.

In some embodiments, the methods described herein can prevent majoradverse cardiac events. In some embodiments, the adverse cardiac eventscan include, but are not limited to cardiovascular death, myocardialinfarction and stroke. In some embodiments, the methods can be used toprevent stroke and systemic embolism in adult patients. In someembodiments, the patients have non-valvular atrial fibrillation (AF)with one or more risk factors. In some embodiments, the methods can beused to prevent or treat pulmonary embolism (PE) in adults. In someembodiments, the methods can be used to prevent or treat deep veinthrombosis (DVT) in adults. In some embodiments, the methods can be usedto concurrently prevent or treat recurrent deep vein thrombosis (DVT)and pulmonary embolism (PE) in adults. In some embodiments, the methodscan be used to prevent or treat venous thromboembolism (VTE) in adultpatients. In other embodiments, the adult patients undergo elective hipreplacement surgery.

In some embodiments, the methods can be used to prevent or treat venousthromboembolism (VTE) in adult patients. In other embodiments, the adultpatients undergo elective knee replacement surgery. In some embodiments,the methods can be used to prevent or treat atherothrombotic events. Insome embodiments, the atherothrombotic events can include but are notlimited to cardiovascular death, myocardial infarction or stroke. Insome embodiments, the prevention or treatment can be after an AcuteCoronary Syndrome in adult patients. In some embodiments, the adultpatients have elevated cardiac biomarkers. In other embodiments, theadult patients have no prior stroke or transient ischaemic attack (TIA)when co-administered with acetylsalicylic acid (ASA) alone (ASA is alsoknown as aspirin). In some embodiments, the adult patients have no priorstroke or transient ischaemic attack (TIA) when co-administered withacetylsalicylic acid (ASA) plus clopidogrel. In some embodiments, theadult patients have no prior stroke or transient ischaemic attack (TIA)when co-administered with acetylsalicylic acid (ASA) plus ticlopidine.

Renal Status

In any of the various embodiments disclosed herein, the patient who isconcomitantly administered rivaroxaban, aspirin, and verapamil can havenormal renal function.

In any of the various embodiments disclosed herein, the patient who isconcomitantly administered rivaroxaban, aspirin, and verapamil can bemildly renally impaired.

In any of the various embodiments disclosed herein, the patient who isconcomitantly administered rivaroxaban, aspirin, and verapamil can havemoderate renal impairment.

In any of the various embodiments disclosed herein, the patient who isconcomitantly administered rivaroxaban, aspirin, and verapamil can havesevere renal impairment.

In some embodiments, the patient has a CL_(Cr) of less than or equal toabout 89 mL/min. In some embodiments, the patient has a CL_(Cr) of lessthan or equal to about 79 mL/min. In some embodiments, the patient has aCL_(Cr) of 60-89 mL/min. In some embodiments, the patient has a CL_(Cr)of 30-59 mL/min. In some embodiments, the patient has a CL_(Cr) of 15-29mL/min.

EMBODIMENTS

1. A method of treating a patient in need of treatment with rivaroxaban,comprising:

(a) administering about 100 to about 480 mg of verapamil daily to thepatient;

(b) administering about 75 mg to about 325 mg of aspirin to the patient;and

(c) administering about 0 mg to less than about 5 mg of rivaroxaban tothe patient.

2. The method of embodiment 1, wherein the dose of verapamiladministered in step (a) is 120, 240, 360, or 480 mg.3. The method of embodiment 1, wherein the dose of aspirin administeredin step (b) is 100 mg.4. The method of embodiment 3, wherein the patient is administered 100mg of aspirin once daily.5. The method of embodiment 1, wherein the patient is administered 2.5mg of rivaroxaban once daily, wherein at least a portion of the 2.5 mgdose of rivaroxaban is administered in a delayed release or extendedrelease formulation.6. The method of embodiment 1, wherein the dose of rivaroxabanadministered in step (c) is about 0.5 mg to less than 2.5 mg ofrivaroxaban.7. The method of embodiment 6, wherein the dose of rivaroxaban isadministered in an immediate release or rapid release formulation.8. The method of embodiment 1, wherein the dose of rivaroxabanadministered in step (c) ranges from about 15% to about 95% of the doserecommended for an otherwise identical patient who is not concomitantlyadministered verapamil.9. The method of embodiments 1, 6, 7, or 8, wherein the dose ofrivaroxaban administered in step (c) ranges from about 0.5 mg to about2.0 mg.10. The method of any of embodiments 1 or 6-9, wherein the dose ofrivaroxaban administered in step (c) is selected from the groupconsisting of about 0.5 mg, about 0.75 mg, about 1.0 mg, about 1.25 mg,about 1.5 mg, about 1.75 mg, and about 2.0 mg.11. The method of any of embodiments 1 or 6-10, wherein the patient isadministered the dose rivaroxaban twice daily.12. The method of any of embodiments 1-11, wherein the total daily doseof rivaroxaban administered to the patient is less than 5 mg.13. The method of embodiment 12, wherein the total daily dose ofrivaroxaban administered to the patient is about 0.5 mg, about 0.75 mg,about 1.0 mg, about 1.25 mg, about 1.5 mg, about 1.75 mg, about 2.0 mg,about 2.25 mg, about 2.5 mg, about 2.75 mg, about 3.0 mg, about 3.25 mg,about 3.5 mg, about 3.75 mg, about 4.0 mg, about 4.25 mg, about 4.5 mg,or about 4.75 mg.14. The method of embodiment 1, wherein the dose of rivaroxabanadministered in step (c) is 0 mg.15. The method of embodiment 1, wherein after administering the dose ofrivaroxaban, the patient has at least one of the followingcharacteristics:

(i) a geometric mean of an area under the plasma concentration-timecurve (AUC) of rivaroxaban in the range of from about 80% of about 165.4μg·h/L to about 125% of about 551.9 μg·h/L after a single dose ofrivaroxaban;

(ii) a geometric mean of a maximum blood plasma concentration (C_(max))of rivaroxaban in the range of from about 80% of 28.6 μg/L to about 125%of 103.0 μg/L after a single dose of rivaroxaban;

(iii) a risk of major bleeding of no more than about 4.5%; or

(iv) a prothrombin time of 20-30 seconds.

16. The method of embodiment 1, wherein after administering the dose ofrivaroxaban, the patient has at least one of the followingcharacteristics:

(i) a geometric mean AUC of rivaroxaban that is less than 1064.25 μg·h/Lafter a single dose of rivaroxaban; and

(ii) a geometric mean C_(max) of rivaroxaban that is less than 181.25μg/L after a single dose of rivaroxaban;

(iii) a risk of major bleeding of no more than about 4.5%; or

(iv) a prothrombin time of 20-30 seconds.

17. The method of embodiment 1, wherein the patient is treated for adisease or condition selected from the group consisting of: decreasingthe risk of major cardiovascular events (death, myocardial infarction,or stroke) in patients with chronic coronary and/or peripheral arterydisease, reducing the risk of acute limb ischemia in patients withperipheral artery disease, decreasing the risk of major cardiovascularevents (death, myocardial infarction, or stroke) in patients with acutecoronary syndrome, and preventing and treating venous thromboembolism incancer patients or patients with active cancer (also referred to ascancer-associated venous thromboembolism).18. The method of any of embodiments 1-13 and 15-17, wherein the patientexperiences an increase in the risk of internal bleeding of no more thanabout 5% compared to an otherwise identical patient that wasadministered aspirin alone.19. The method of any of embodiments 1-13 and 15-18, wherein thepatient's risk of a major bleeding event is less than about 5%.20. The method of any of embodiments 1-13 and 15-19, and the efficacy intreating the condition is similar to the efficacy observed for the samecondition in an otherwise identical patient that was treated with 2.5 mgof rivaroxaban but was not treated with verapamil.21. The method of embodiment 1, wherein the patient is not renallyimpaired.22. The method of embodiment 1, wherein the patient is mildly toseverely renally impaired.23. The method of embodiment 22, wherein the patient is mildly renallyimpaired.24. The method of embodiment 22, wherein the patient is moderatelyrenally impaired.25. The method of embodiment 22, wherein the patient is severely renallyimpaired.26. The method of embodiment 1, wherein the patient has a CL_(Cr) ofless than or equal to about 89 mL/min.27. The method of embodiment 1, wherein the patient has a CL_(Cr) ofless than or equal to about 79 mL/min.28. The method of embodiment 1, wherein the patient has a CL_(Cr) of60-89 mL/min.29. The method of embodiment 1, wherein the patient has a CL_(Cr) of30-59 mL/min.30. The method of embodiment 1, wherein the patient has a CL_(Cr) of15-29 mL/min.

EXAMPLES Example 1. Oral Verapamil and Rivaroxaban Drug-Drug Interaction

This example illustrates the drug-drug interaction that occurs when apatient is concomitantly administered verapamil and rivaroxaban, whichapproximately doubles the patient's exposure to rivaroxaban. That is,this study shows that the pharmacokinetic parameters of a patientadministered 20 mg of rivaroxaban in combination with verapamil areapproximately equal those of a patient that was administered 40 mg ofrivaroxaban in the absence of verapamil. Therefore, a patient that isco-administered 2.5 mg of rivaroxaban with rivaroxaban would actuallyhave the pharmacokinetic profile of a 5 mg dose of rivaroxaban.

A volunteer patient trial using both healthy and mildly renally impairedsubjects is conducted in order to assess the pharmacokinetic andpharmacodynamic consequences of rivaroxaban and verapamil concomitantadministration. This initial study is a non-randomized, open labelcontrolled study of the rivaroxaban-verapamil drug-drug interaction.

During the initial portion of the study, patients are administered asingle 20 mg dose of rivaroxaban with their breakfast withoutco-administration of verapamil. These patients are subjected to variousone-time and longitudinal pharmacokinetic (PK) and pharmacodynamic (PD)analyses. Patient plasma levels of rivaroxaban are tracked for at least72 hours after receiving a rivaroxaban dose. C_(max) and AUC values foreach dose are calculated. Patients also undergo a general physical examto determine overall health and well-being.

Additional pharmacodynamic metrics are also gathered for each patient,including, but not limited to: prothrombin time (using the STA®Neoplastin® method) and Factor Xa activity. Protocols for each of theseanalyses have been described in Nielsen et al 2015. Renal Function andnon-vitamin K oral anticoagulants in comparison with warfarin on safetyand efficacy outcomes in atrial fibrillation patients: a systemic reviewand meta-regression analysis. Clin Res Cardiol May 104(5): 418-429).

During the second portion of the study, patients are administered averapamil dose of 180 mg on Day 8, 240 mg on Day 9, and 360 mg on Days10-15 to achieve steady state plasma concentrations of verapamil. On Day15, patients will receive 360 mg verapamil together with the 20 mgrivaroxaban doses described for the initial portion of the study. Allthe pharmacokinetic and pharmacodynamics analyses are repeated onpatients receiving this treatment.

PK and PD results for the rivaroxaban single treatment andrivaroxaban-verapamil concomitant treatment are compared to determinethe safety profile of the resulting rivaroxaban doses.

The results show that concomitant administration of verapamil withrivaroxaban produces higher rivaroxaban plasma concentrations, prolongedPT, and increased Factor Xa inhibition.

Example 2. Pharmacokinetics and Plasma Rivaroxaban Concentrations inSubjects with Mild Renal Impairment and Normal Renal Function

To estimate the effect of steady-state verapamil on thepharmacokinetics, pharmacodynamics, and safety of rivaroxaban, a studywas conducted on subjects with either mild renal impairment or normalrenal function. Subjects with either mild renal impairment or withnormal renal function were enrolled. Subjects received a single 20 mgdose of rivaroxaban (“Period I”) on the first day of the study, andafter a washout period, a single 20 mg dose of rivaroxaban and a 360 mgdose of verapamil at steady state (“Period III”).

Renal function of the subjects was determined by measuring creatinineclearance (CLcr) rates. Subjects who had CLcr ≥90 mL/min werecategorized as having normal renal function whereas subjects who hadCLcr 50-79 mL/min were categorized as mildly renally impaired. Bloodsamples were collected and processed according to the standardprotocols. Plasma rivaroxaban concentrations were measured on Day 1 ofthe study at 0.5, 1, 2, 3, 4, 6, 8, and 12 hours, Day 2 at 24 and 36hours, Day 3 at 48 hours, and Day 4 at 72 hours and are shown in Tables1A-8 below.

TABLE 1A Plasma Rivaroxaban Concentration-Time Data and SummaryStatistics for Treatment Period I Separated by Renal Function Group (PKAnalysis Set) Group 1: Mild Renal Impairment, (N = 14) Time Point DayDay Day Day Day Day Day 1, 1, 1, 1, 1, 1, 1, Subject 0 hr 0.5 hr 1 hr 2hr 3 hr 4 hr 6 hr 1101 0 83.8 151 251 241 218 114 1102 0 207 278 207 197204 161 1103 0 170 187 185 196 181 126 1104 0 235 218 184 199 182 1191106 0 24.0 153 232 238 172 172 1108 0 174 168 170 297 344 274 1110 0201 306 248 206 219 157 1111 0 245 247 211 268 247 164 1114 0 215 308232 184 192 103 1115 0 170 133 187 215 190 133 1116 0 130 132 120 97.990.6 55.7 1118 0 326 448 333 315 316 128 2101 0 208 217 208 176 165 1142104 0 23.4 25.7 40.6 55.8 79.6 232 n 14 14 14 14 14 14 14 n < LLOQ 14 00 0 0 0 0 CV % NC 48.8 48.3 33.4 33.6 35.7 37.3 AM 0 172 212 201 206 200147 SD 0 84.0 102 66.9 69.2 71.5 54.6 Median 0 188 202 208 202 191 130Minimum 0 23.4 25.7 40.6 55.8 79.6 55.7 Maximum 0 326 448 333 315 344274 Lower limit of quantitation (LLOQ) = 5 (μg/L). N: Number ofsubjects, n: Number of non-missing observations, hr: Hour, BLQ: Belowthe limit of quantitation, AM: Arithmetic mean, SD: Standard deviation.BLQ values are treated as zero. NC = Not calculated Values expressed inμg/L CV % = (SD/Mean) × 100, where SD and mean are standard deviationand arithmetic mean of untransformed data. Summary statistics for Day 1,0 hr are based on greater than 30% imputed values. n < LLOQ = Number ofBLQs imputed as zero.

TABLE 1B Plasma Rivaroxaban Concentration-Time Data and SummaryStatistics for Treatment Period I Separated by Renal Function Group (PKAnalysis Set) Group 1: Mild Renal Impairment, (N = 14) Time Point DayDay Day Day Day Day 1, 1, 2, 2, 3, 4, Subject 8 hr 12 hr 24 hr 36 hr 48hr 72 hr 1101 76.8 52.9 36.5 14.9 8.49 0 1102 131 84.9 53.7 10.0 9.67 01103 124 61.5 52.9 8.92 0 0 1104 89.5 38.8 41.9 10.8 6.49 0 1106 15792.7 19.9 12.1 6.13 0 1108 221 132 50.3 17.9 11.4 0 1110 143 89.1 52.521.7 17.0 0 1111 125 72.7 38.6 18.5 15.5 0 1114 66.4 66.8 39.1 14.8 6.710 1115 122 103 33.9 11.2 0 0 1116 47.6 29.4 10.1 0 0 0 1118 102 49.942.2 21.5 21.4 12.2 2101 90.2 51.9 21.1 7.44 7.10 0 2104 223 97.7 18.0 00 0 n 14 14 14 14 14 14 n < LLOQ 0 0 0 2 4 13 CV % 42.2 38.7 39.1 56.186.2 374 AM 123 73.1 36.5 12.1 7.85 0.871 SD 51.8 28.3 14.3 6.80 6.773.26 Median 123 69.8 38.8 11.6 6.90 0 Minimum 47.6 29.4 10.1 0 0 0Maximum 223 132 53.7 21.7 21.4 12.2 Lower limit of quantitation (LLOQ) =5 (μg/L). N: Number of subjects, n: Number of non-missing observations,hr: Hour, BLQ: Below the limit of quantitation, AM: Arithmetic mean, SD:Standard deviation. BLQ values are treated as zero. Values expressed inμg/L CV % = (SD/Mean) × 100, where SD and mean are standard deviationand arithmetic mean of untransformed data. Summary statistics for Day 4,72 hr are based on greater than 30% imputed values. n < LLOQ = Number ofBLQs imputed as zero.

TABLE 2A Plasma Rivaroxaban Concentration-Time Data and SummaryStatistics for Treatment Period I Separated by Renal Function GroupExcluding Outlier Sample (PK Analysis Set) Group 2: Normal RenalFunction, (N = 13) Time Point Day Day Day Day Day Day Day 1, 1, 1, 1, 1,1, 1, Subject 0 hr 0.5 hr 1 hr 2 hr 3 hr 4 hr 6 hr 01105 0 107 160 187290 336 230 01107 0 194 252 229 242 297 172 01109 0 117 249 204 307 276162 01112 0 71.8 175 195 183 169 119 01113 0 169 178 163 183 148 91.901117 0 429 297 195 164 155 116 01119 0 197 175 208 263 352 180 01120 060.3 214 196 211 187 131 01121 0 218 195 151 133 115 67.5 02102 0 67.1142 212 202 171 142 02103 0 129 214 201 230 183 133 02105 0 43.4 104 188245 292 256 02106 0 26.2 80.5 141 215 266 218 n 13 13 13 13 13 13 13 n <LLOQ 13 0 0 0 0 0 0 CV % NC 75.9 32.0 13.1 22.4 34.8 35.5 AM 0 141 187190 221 227 155 SD 0 107 59.9 24.8 49.5 78.8 55.1 Median 0 117 178 195215 187 142 Minimum 0 26.2 80.5 141 133 115 67.5 Maximum 0 429 297 229307 352 256 Lower limit of quantitation (LLOQ) = 5 (μg/L). N: Number ofsubjects, n: Number of non-missing observations, hr: Hour, BLQ: Belowthe limit of quantitation, AM: Arithmetic mean, SD: Standard deviation.% CVb = 100 * SQRT [ex[(S{circumflex over ( )}2) − 1]], where S is thestandard deviation of the data on a log scale. BLQ values are treated aszero. NC = Not calculated Values expressed in μg/L Summary statisticsfor Day 1, 0 hr are based on greater than 30% imputed values. n < LLOQ =Number of BLQs imputed as zero.

TABLE 2B Plasma Rivaroxaban Concentration-Time Data and SummaryStatistics for Treatment Period I Separated by Renal Function GroupExcluding Outlier Sample (PK Analysis Set) Group 2: Normal RenalFunction, (N = 13) Time Point Day Day Day Day Day Day 1, 1, 2, 2, 3, 4,Subject 8 hr 12 hr 24 hr 36 hr 48 hr 72 hr 01105 202 94.7 27.1 9.61 0 001107 114 72.3 25.1 5.30 0 0 01109 138 110 23.8 0 0 0 01112 88.9 53.920.0 6.02 0 0 01113 71.5 26.5 21.3 7.48 0 0 01117 104 47.3 32.0 20.614.3 0 01119 138 77.3 24.3 7.19 93.1† 0 01120 114 50.7 17.3 5.98 0 001121 52.7 38.0 19.4 9.86 7.00 0 02102 109 66.6 22.6 5.26 0 0 02103 13442.6 16.6 8.97 5.53 0 02105 183 91.9 25.2 8.16 5.53 0 02106 150 86.935.4 12.4 8.51 0 n 13 13 13 13 12 13 n < LLOQ 0 0 0 1 7 13 CV % 33.738.2 22.7 58.0 139 NC AM 123 66.1 23.9 8.22 3.41 0 SD 41.4 25.3 5.424.76 4.75 0 Median 114 66.6 23.8 7.48 0 0 Minimum 52.7 26.5 16.6 0 0 0Maximum 202 110 35.4 20.6 14.3 0 Lower limit of quantitation (LLOQ) = 5(μg/L). N: Number of subjects, n: Number of non-missing observations,hr: Hour, BLQ: Below the limit of quantitation, AM: Arithmetic mean, SD:Standard deviation. % CVb = 100 * SQRT [ex[(S{circumflex over ( )}2) −1]], where S is the standard deviation of the data on a log scale. BLQvalues are treated as zero. NS = No sample; NC = Not calculated Valuesexpressed in μg/L †Outlier sample excluded from summary statiticsSummary statistics for Day 3, 48 hr, Day 4, 72 hr are based on greaterthan 30% imputed values. n < LLOQ = Number of BLQs imputed as zero.

TABLE 3A Plasma Rivaroxaban Concentration-Time Data and SummaryStatistics for Treatment Period III Separated by Renal Function Group(PK Analysis Set) Group 1: Mild Renal Impairment, (N = 11) Time PointDay Day Day Day Day Day Day 1, 1, 1, 1, 1, 1, 1, Subject 0 hr 0.5 hr 1hr 2 hr 3 hr 4 hr 6 hr 1101 0 154 211 196 238 247 154 1103 0 203 293 300285 257 188 1104 0 278 260 268 276 214 164 1106 0 10.2 42.6 109 213 280233 1108 0 158 192 263 303 303 269 1111 0 242 272 278 280 327 285 1114 0249 218 279 250 226 170 1116 0 185 192 191 203 242 124 1118 0 349 387429 429 458 209 2101 0 202 190 149 134 160 99.7 2104 0 136 113 132 117126 135 n 11 11 11 11 11 11 11 n < LLOQ 11 0 0 0 0 0 0 CV % NC 44.4 42.239.1 34.3 34.1 32.1 AM 0 197 216 236 248 258 185 SD 0 87.5 91.0 92.185.1 88.1 59.2 Median 0 202 211 263 250 247 170 Minimum 0 10.2 42.6 109117 126 99.7 Maximum 0 349 387 429 429 458 285 Lower limit ofquantitation (LLOQ) = 5 (μg/L). N: Number of subjects, n: Number ofnon-missing observations, hr: Hour, BLQ: Below the limit ofquantitation, AM: Arithmetic mean, SD: Standard deviation. BLQ valuesare treated as zero. NC = Not calculated Values expressed in μg/L CV % =(SD/Mean) × 100, where SD and mean are standard deviation and arithmeticmean of untransformed data. Summary statistics for Day 1, 0 hr are basedon greater than 30% imputed values. n < LLOQ = Number of BLQs imputed aszero.

TABLE 3B Plasma Rivaroxaban Concentration-Time Data and SummaryStatistics for Treatment Period III Separated by Renal Function Group(PK Analysis Set) Group 1: Mild Renal Impairment, (N = 11) Time PointDay Day Day Day Day Day 1, 1, 2, 2, 3, 4, Subject 8 hr 12 hr 24 hr 36 hr48 hr 72 hr 1101 125 77.7 36.0 11.1 8.48 0 1103 148 96.0 61.9 20.2 11.10 1104 194 88.6 45.5 25.0 12.9 8.27 1106 251 145 34.8 21.6 8.48 0 1108222 154 78.5 33.0 27.4 10.6 1111 268 159 76.8 29.1 23.0 9.37 1114 12655.4 27.6 14.2 17.0 8.69 1116 106 67.7 30.0 13.9 8.27 0 1118 179 13468.5 34.9 31.2 13.1 2101 78.5 75.8 62.2 31.1 14.7 0 2104 118 95.0 46.627.0 19.1 7.48 n 11 11 11 11 11 11 n < LLOQ 0 0 0 0 0 5 CV % 37.8 35.436.2 34.5 47.9 99.6 AM 165 104 51.7 23.7 16.5 5.23 SD 62.3 37.0 18.78.19 7.91 5.21 Median 148 95.0 46.6 25.0 14.7 7.48 Minimum 78.5 55.427.6 11.1 8.27 0 Maximum 268 159 78.5 34.9 31.2 13.1 Lower limit ofquantitation (LLOQ) = 5 (μg/L). N: Number of subjects, n: Number ofnon-missing observations, hr: Hour, BLQ: Below the limit ofquantitation, AM: Arithmetic mean, SD: Standard deviation. BLQ valuesare treated as zero. Values expressed in μg/L CV % = (SD/Mean) × 100,where SD and mean are standard deviation and arithmetic mean ofuntransformed data. Summary statistics for Day 4, 72 hr are based ongreater than 30% imputed values. n < LLOQ = Number of BLQs imputed aszero.

TABLE 4A Plasma Rivaroxaban Concentration-Time Data and SummaryStatistics for Treatment Period III Separated by Renal Function Group(PK Analysis Set) Group 2: Normal Renal Function, (N = 10) Time PointDay Day Day Day Day Day Day 1, 1, 1, 1, 1, 1, 1, Subject 0 hr 0.5 hr 1hr 2 hr 3 hr 4 hr 6 hr 1105 0 179 185 208 267 383 268 1107 0 179 159 220331 296 303 1109 0 198 236 302 264 292 205 1112 0 151 163 160 163 143116 1119 0 148 206 314 314 348 287 1120 0 131 137 236 260 257 202 1121 0178 201 208 178 154 103 2102 0 125 141 225 220 224 193 2103 0 214 269232 225 201 177 2106 0 50.9 122 284 310 394 227 n 10 10 10 10 10 10 10 n< LLOQ 10 0 0 0 0 0 0 CV % NC 29.9 25.7 19.9 22.4 33.2 32.0 AM 0 155 182239 253 269 208 SD 0 46.4 46.7 47.6 56.8 89.5 66.6 Median 0 164 174 228262 274 204 Minimum 0 50.9 122 160 163 143 103 Maximum 0 214 269 314 331394 303 Lower limit of quantitation (LLOQ) = 5 (μg/L). N: Number ofsubjects, n: Number of non-missing observations, hr: Hour, BLQ: Belowthe limit of quantitation, AM: Arithmetic mean, SD: Standard deviation.BLQ values are treated as zero. NC = Not calculated Values expressed inμg/L CV % = (SD/Mean) × 100, where SD and mean are standard deviationand arithmetic mean of untransformed data. Summary statistics for Day 1,0 hr are based on greater than 30% imputed values. n < LLOQ = Number ofBLQs imputed as zero.

TABLE 4B Plasma Rivaroxaban Concentration-Time Data and SummaryStatistics for Treatment Period III Separated by Renal Function Group(PK Analysis Set) Group 2: Normal Renal Function, (N = 10) Time PointDay Day Day Day Day Day 1, 1, 2, 2, 3, 4, Subject 8 hr 12 hr 24 hr 36 hr48 hr 72 hr 1105 197 85.9 42.3 13.3 5.04 0 1107 182 121 41.3 11.7 6.36 01109 143 110 42.5 17.4 10.8 0 1112 94.9 78.7 50.9 12.3 8.87 0 1119 262145 27.3 8.79 0 0 1120 119 62.8 27.4 8.99 0 0 1121 73.9 50.8 27.1 14.812.2 0 2102 160 102 48.4 19.5 10.7 0 2103 248 98.4 40.6 12.1 6.73 6.422106 173 125 60.2 22.8 13.0 9.22 n 10 10 10 10 10 10 n < LLOQ 0 0 0 0 28 CV % 36.9 29.7 27.0 31.9 63.3 215 AM 165 98.0 40.8 14.2 7.37 1.56 SD61.0 29.1 11.0 4.52 4.66 3.36 Median 166 100 41.8 12.8 7.80 0 Minimum73.9 50.8 27.1 8.79 0 0 Maximum 262 145 60.2 22.8 13.0 9.22 Lower limitof quantitation (LLOQ) = 5 (μg/L). N: Number of subjects, n: Number ofnon-missing observations, hr: Hour, BLQ: Below the limit ofquantitation, AM: Arithmetic mean, SD: Standard deviation. BLQ valuesare treated as zero. Values expressed in μg/L CV % = (SD/Mean) × 100,where SD and mean are standard deviation and arithmetic mean ofuntransformed data. Summary statistics for Day 4, 72 hr are based ongreater than 30% imputed values. n < LLOQ = Number of BLQs imputed aszero.

Plasma rivaroxaban pharmacokinetic data for both normal renal functiongroups and mild renal impairment groups who received both rivaroxabanalone (Period I) and rivaroxaban and verapamil (Period III) arepresented in the Tables below:

TABLE 5 Plasma Rivaroxaban Noncompartmental Pharmacokinetic Parametersand Summary Statistics for Treatment Period I Separated by RenalFunction Group (PK Analysis Set) Group 1: Mild Renal Impairment, (N =14) C_(max) t_(max) AUC_(0-t) AUC_(0-inf) K_(el) t_(1/2) CL/F CL/F/kgV_(z)/F Subject (ng/mL) (hr) (hr*ng/mL) (hr*ng/mL) (1/hr) (hr) (L/hr)((L/hr)/kg) (L) 01101 251 2.00 2530 2680 0.0542 12.8 7.45 0.113 13801102 278 1.00 3240 3370 0.0734 9.44 5.93 0.0803 80.8 01103 196 3.002690 2800 0.0825 8.40 7.14 0.114 86.5 01104 235 0.50 2430 2510 0.07529.21 7.96 0.156 106 01106 238 3.00 2830 2960 0.0491 14.1 6.76 0.0845 13801108 344 4.00 4350 4500 0.0778 8.91 4.45 0.0496 57.2 01110 306 1.003560 3840 0.0601 11.5 5.20 0.0670 86.5 01111 268 3.00 3250 3600 0.044715.5 5.55 0.0841 124 01114 308 1.00 2670 2760 0.0734 9.44 7.24 0.13798.7 01115 215 3.00 2800 2920 0.0925 7.50 6.84 0.0946 74.0 01116 1321.00 1070 1170 0.0954 7.26 17.0 0.253 179 01118 448 1.00 3880 43900.0240 28.9 4.56 0.0828 190 02101 217 1.00 2200 2290 0.0786 8.82 8.74 NR111 02104 232 6.00 2290 2400 0.155 4.47 8.32 NR 53.7 n 14 14 14 14 14 1414 12 14 GM* 252 NC 2720 2880 0.0683 10.2 6.95 0.100 102 CVb % 28.7 NC28.3 29.1 41.1 52.5 41.9 49.2 38.0 AM 262 NC 2840 3010 0.0740 11.2 7.370.110 109 SD 75.2 NC 804 878 0.0304 5.87 3.09 0.0540 41.3 Median 2441.50 2750 2860 0.0743 9.32 6.99 0.0896 102 Minimum 132 0.50 1070 11700.0240 4.47 4.45 0.0496 53.7 Maximum 448 6.00 4350 4500 0.155 28.9 17.00.253 190 *Calculated using log transformed data. N: Number of subjects,n: Number of non-missing observations, GM: Geometric mean, AM:Arithmetic mean, SD: Standard deviation, NR = Not reported; NC = Notcalculated % CVb = 100 * SQRT [ex[(S{circumflex over ( )}2) − 1]], whereS is the standard deviation of the data on a log scale.

TABLE 6 Plasma Rivaroxaban Noncompartmental Pharmacokinetic Parametersand Summary Statistics for Treatment Period I Separated by RenalFunction Group Excluding Outlier Sample (PK Analysis Set) Group 2:Normal Renal Function, (N = 13) C_(max) t_(max) AUC_(0-t) AUC_(0-inf)K_(el) t_(1/2) CL/F CL/F/kg V_(z)/F Subject (ng/mL) (hr) (hr*ng/mL)(hr*ng/mL) (1/hr) (hr) (L/hr) ((L/hr)/kg) (L) 01105 336 4.08 3370 34700.0955 7.26 5.76 0.0696 60.4 01107 297 4.00 2800 2850 0.110 6.29 7.020.0817 63.7 01109 307 3.00 2930 3150 0.108 6.39 6.35 0.0829 58.6 01112195 2.00 2010 2070 0.0938 7.39 9.64 0.0960 103 01113 183 3.00 1700 17900.0839 8.26 11.2 0.197 133 01117 429 0.50 2670 3090 0.0336 20.6 6.460.0998 193 01119 352 4.10 3560 4440 0.106 6.56 4.50 0.0579 42.6 01120214 1.00 2130 2200 0.0891 7.78 9.10 0.107 102 01121 218 0.50 1700 18400.0511 13.6 10.9 0.177 213 02102 212 2.00 2260 2310 0.108 6.44 8.68 NR80.5 02103 230 3.00 2280 2400 0.0458 15.1 8.33 NR 182 02105 292 4.003200 3260 0.0939 7.38 6.14 NR 65.4 02106 266 4.00 3040 3150 0.0726 9.556.34 NR 87.4 n 13 13 13 13 13 13 13 9 13 GM* 263 NC 2520 2680 0.07938.74 7.47 0.0997 94.2 CVb % 26.7 NC 24.0 27.4 30.5 46.3 26.8 44.3 53.0AM 272 NC 2590 2770 0.0839 9.43 7.72 0.108 106 SD 72.4 NC 621 760 0.02564.37 2.07 0.0476 56.4 Median 266 3.00 2670 2850 0.0938 7.39 7.02 0.096087.4 Minimum 183 0.50 1700 1790 0.0336 6.29 4.50 0.0579 42.6 Maximum 4294.10 3560 4440 0.110 20.6 11.2 0.197 213 *Calculated using logtransformed data. N: Number of subjects, n: Number of non-missingobservations, GM: Geometric mean, AM: Arithmetic mean, SD: Standarddeviation, NR = Not reported; NC = Not calculated % CVb = 100 * SQRT[ex[(S{circumflex over ( )}2) − 1]], where S is the standard deviationof the data on a log scale. The Period 1, 48 hr timepoint for subject01119 was excluded as an outlier from the analysis.

TABLE 7 Plasma Rivaroxaban Noncompartmental Pharmacokinetic Parametersand Summary Statistics for Treatment Period III Separated by RenalFunction Group (PK Analysis Set) Group 1: Mild Renal Impairment, (N =11) C_(max) t_(max) AUC_(0-t) AUC_(0-inf) K_(el) t_(1/2) CL/F CL/F/kgV_(z)/F Subject (ng/mL) (hr) (hr*ng/mL) (hr*ng/mL) (1/hr) (hr) (L/hr)((L/hr)/kg) (L) 01101 247 4.00 2950 3070 0.0721 9.61 6.51 0.0991 90.301103 300 2.00 3920 4090 0.0664 10.4 4.89 0.0781 73.6 01104 278 0.503990 4140 0.0542 12.8 4.83 0.0949 89.1 01106 280 4.00 3870 3980 0.08208.46 5.03 0.0628 61.3 01108 303 3.00 5630 5840 0.0503 13.8 3.42 0.038268.1 01111 327 4.00 5810 6090 0.0323 21.4 3.28 0.0497 102 01114 279 2.003230 3530 0.0283 24.5 5.66 0.107 200 01116 242 4.00 2680 2820 0.059011.7 7.08 0.105 120 01118 458 4.00 5990 6300 0.0418 16.6 3.17 0.057776.0 02101 202 0.50 3010 3260 0.0598 11.6 6.14 NR 103 02104 136 0.503280 3480 0.0374 18.5 5.74 NR 154 n 11 11 11 11 11 11 11 9 11 GM* 267 NC3880 4080 0.0504 13.7 4.90 0.0728 97.1 CVb % 28.9 NC 30.2 29.6 32.0 35.626.2 33.6 40.2 AM 277 NC 4030 4240 0.0530 14.5 5.07 0.0770 103 SD 80.1NC 1220 1260 0.0170 5.16 1.33 0.0259 41.5 Median 279 3.00 3870 39800.0542 12.8 5.03 0.0781 90.3 Minimum 136 0.50 2680 2820 0.0283 8.46 3.170.0382 61.3 Maximum 458 4.00 5990 6300 0.0820 24.5 7.08 0.107 200*Calculated using log transformed data. N: Number of subjects, n: Numberof non-missing observations, GM: Geometric mean, AM: Arithmetic mean,SD: Standard deviation. NR = Not reported; NC = Not calculated % CVb =100 * SQRT [ex[(S{circumflex over ( )}2) − 1]], where S is the standarddeviation of the data on a log scale.

TABLE 8 Plasma Rivaroxaban Noncompartmental Pharmacokinetic Parametersand Summary Statistics for Treatment Period III Separated by RenalFunction Group (PK Analysis Set) Group 2: Normal Renal Function, (N =10) C_(max) t_(max) AUC_(0-t) AUC_(0-inf) K_(el) t_(1/2) CL/F CL/F/kgV_(z)/F Subject (ng/mL) (hr) (hr*ng/mL) (hr*ng/mL) (1/hr) (hr) (L/hr)((L/hr)/kg) (L) 01105 383 4.00 3780 3840 0.0884 7.84 5.21 0.0629 58.901107 331 3.00 3990 4060 0.0866 8.00 4.92 0.0573 56.9 01109 302 2.003770 3930 0.0672 10.3 5.08 0.0664 75.7 01112 163 1.00 2690 2820 0.065610.6 7.08 0.0705 108 01119 348 4.00 4260 4330 0.121 5.71 4.61 0.059438.0 01120 260 3.00 2690 2800 0.0810 8.55 7.14 0.0839 88.1 01121 2082.00 2260 2530 0.0456 15.2 7.90 0.128 173 02102 225 2.00 3500 36700.0643 10.8 5.46 NR 84.9 02103 269 1.00 3780 3880 0.0614 11.3 5.15 NR83.9 02106 394 4.00 4620 4800 0.0511 13.6 4.17 NR 81.6 n 10 10 10 10 1010 10 7 10 GM* 278 NC 3460 3600 0.0705 9.83 5.56 0.0727 78.8 CVb % 26.6NC 21.4 19.9 30.0 27.6 21.9 33.0 43.2 AM 288 NC 3530 3670 0.0732 10.25.67 0.0755 84.9 SD 76.8 NC 755 728 0.0220 2.82 1.24 0.0249 36.7 Median286 2.50 3780 3860 0.0664 10.4 5.18 0.0664 82.7 Minimum 163 1.00 22602530 0.0456 5.71 4.17 0.0573 38.0 Maximum 394 4.00 4620 4800 0.121 15.27.90 0.128 173 *Calculated using log transformed data. N: Number ofsubjects, n: Number of non-missing observations, GM: Geometric mean, AM:Arithmetic mean, SD: Standard deviation. NR = Not reported; NC = Notcalculated % CVb = 100 * SQRT [ex[(S{circumflex over ( )}2) − 1]], whereS is the standard deviation of the data on a log scale.

Example 3. Plasma Rivaroxaban Concentrations and the Risk of MajorBleeding in Subjects with Mild Renal Impairment

To evaluate the relationship between the plasma levels of rivaroxabanand the risk of major bleeding, the subjects with mild renalinsufficiency were given a single 20 mg dose of rivaroxaban on the firstday of the study (as described in the study in Example 2). Blood sampleswere collected and processed according to the standard protocols. Plasmarivaroxaban concentrations were measured on Day 1 and Day 15. As shownin FIGS. 1 and 2, the risk of major bleeding based on PT values, werepositively correlated with increased plasma concentrations ofrivaroxaban. The results showed a clear linear relationship between thepharmacokinetics and the pharmacodynamics of rivaroxaban in subjectswith normal renal function and mild renal insufficiency.

The steady state area under the curve (AUC) of plasma rivaroxaban insubjects with either normal renal function or mild renal impairmentunder different treatment regimens was also examined. As shown in FIG.3, the leftmost 6 box plots (study 10842) show the distribution of AUCvalues for various dosing levels of rivaroxaban (10 mg, 20 mg, 30 mg, 40mg, 60 mg, and 80 mg, respectively) previously measured in clinicaltrials supporting FDA approval of Xarelto® (rivaroxaban). The next ninebox plots (studies 10993, 10999, 12359, 12680, 11273, 10989, and 11938)in the middle represent subjects treated with a single 20 mg dose ofrivaroxaban under normal, fasted, or fed condition. All show thegeometric mean plus or minus one standard deviation. The last four boxplots show the distribution of AUC values measured in the present study,for subjects with normal renal function (designated “N”) and subjectswith mild renal impairment (designated “MRI”) who were either treatedwith a single 20 mg dose of rivaroxaban (“P1”) or a single 20 mg dose ofrivaroxaban and 360 mg verapamil (“P3”). These four show the geometricmean and the full minimum and maximum subject value range.

The results in FIG. 3 show that the geometric mean in the subjects withmild renal impairment treated with both rivaroxaban and verapamil in thepresent study was about one standard deviation higher than the mean AUClevels in subjects with normal renal function treated with a single 80mg dose of rivaroxaban. The present study shows that subjects with mildrenal impairment who took both rivaroxaban and verapamil had mean AUClevels well above the AUC levels observed in subjects with normal renalfunction treated with a single 20 mg dose of rivaroxaban; that is, suchpatients coadministered rivaroxaban and verapamil have AUC valuessubstantially higher than values currently considered acceptable by theFDA.

Another representation of these data are shown in FIG. 4. Label “A”represents the upper bound of the 90% confidence interval of the steadystate AUC of patients administered 20 mg of rivaroxaban, about 3,792μg·hr/L. Label “B” is the estimated steady state AUC, about 3,404μg·hr/L for patients administered a single 10 mg dose of rivaroxaban incombination with a strong CYP3A4/Pgp inhibitor. Label “C” is the upperboundary of the 90% confidence interval of the steady state AUC level insubjects treated with a single 20 mg dose of rivaroxaban after a meal,about 2,448 μg·hr/L. The remaining 4 box plots are reproduced from FIG.3. FIG. 4 shows that AUC_(inf) values in subjects with mild renalimpairment (“MRI”) treated with a single 20 mg dose of rivaroxaban and360 mg verapamil (P3) are significantly higher than expected fromprevious studies. For example, the geometric mean of the steady stateAUC for such patients was higher than the upper limits of safetyidentified in the FDA's Clinical Pharmacology review for rivaroxaban,demonstrating that a significant portion of the relevant patientpopulation who have mild renal impairment have AUC values fallingoutside of the range accepted by the FDA. Further, the present studyshows that a significant portion of patients with normal renal functiontreated with rivaroxaban and verapamil have plasma levels significantlyhigher than the upper boundary of the 90% confidence interval of thesteady state AUC level in subjects from the rivaroxaban approval studiestreated with a single 20 mg dose of rivaroxaban (Label “C”),demonstrating a higher bleeding risk than is presently recognized in theart. Additionally, the present study shows that patients with mild renalimpairment have plasma levels of rivaroxaban which are significantlyhigher than the upper boundary of the 90% confidence interval of thesteady state AUC level in subjects from the rivaroxaban approval studiestreated with a single 20 mg dose of rivaroxaban (Label “C”),demonstrating a higher bleeding risk than is presently recognized in theart.

FIG. 5 shows that the relationship between steady state rivaroxaban AUCand the risk of major bleeding. Group “a” in FIG. 5 represents theaverage geometric mean of fed subjects across two studies (10989 and11938) who took a single 20 mg rivaroxaban and had an average of AUC ofapproximately 2,026 μg·hr/L, which corresponded to about 3% risk ofmajor bleeding. Group “b” in the FIG. 5 represents subjects with mildrenal impairment who took a single 20 mg rivaroxaban and 360 mgverapamil and had an estimated of AUC_(inf) of approximately 5,469μg·hr/L, which shows that the mild renal impairment caused higheraccumulation of rivaroxaban in the plasma and led to 2.5 times higherthe risk of major bleeding compared to the populations in Group “a”.Group “c” represents the average of the three subjects in Group “b” whohad the highest AUC_(inf), which was about 8,143 μg·hr/L. The risk ofmajor bleeding of the subjects in Group “c” were at least 5 times highercompared to the populations in Group “a” and not even visible on thisscale.

Example 4. Drug-Drug Interaction with Oral Verapamil and 2.5 mg ofRivaroxaban

A control study is performed to determine the presence of DDIs inpatients treated with oral verapamil and rivaroxaban (without aspirin).This study is performed through a University, Hospital, Clinic, or otherfacility with proper approvals and access to subjects and is performedto demonstrate the presence of DDIs. A representative example of asample study is found in Example 1.

This study compares and assesses the pharmacokinetic and pharmacodynamicconsequences of 0.5-2.5 mg of rivaroxaban and various recommended dosesof verapamil when concomitantly administered to patients (e.g., healthyand renally impaired) by measuring blood plasma levels at various timeintervals after dosing.

The outcomes of such a study shows that verapamil causes higherrivaroxaban plasma concentrations, prolonged PT, and increased Factor Xainhibition. Patients are administered 0.5-2.5 mg of rivaroxabanconcomitantly with verapamil (100-480 mg), and blood plasma levels aremeasured and compared to similar (e.g., identical) patients who were notadministered verapamil. Patents concomitantly treated with rivaroxabanand verapamil have a much higher plasma rivaroxaban level than for asimilar (e.g., identical) patient who has not taken verapamil.

In one study, patients are administered a 2.5 mg dose of rivaroxaban andconcomitantly administered verapamil. The blood plasma level ofrivaroxaban for such a patient is equal to or greater than a similarpatient who has taken a 5 mg dose of rivaroxaban and who has not takenverapamil. That is, the average geometric mean of subjects who take asingle dose of rivaroxaban (e.g., 2.5 mg), and verapamil (e.g., 360 mg)have an average AUC of approximately 1064.25 μg·hr/L or greater. Thegeometric mean AUC of rivaroxaban for 5 mg dose of rivaroxaban is1064.25 μg·h/L. Thus, consistent with Example 1, the blood plasma levelsof a patient who is administered 2.5 mg of rivaroxaban and who isconcomitantly administered verapamil is approximately equal to those ofpatient who is administered 5 mg of rivaroxaban.

In another study, patients are administered a 1.75 mg dose ofrivaroxaban and concomitantly administered verapamil. The blood plasmalevel of rivaroxaban for such a patient is approximately equal to asimilar patient who has taken a 2.5 mg dose of rivaroxaban and who hasnot taken verapamil. That is, the average geometric mean of subjects whotake a single dose of rivaroxaban (e.g., 1.75 mg) and verapamil (e.g.,360 mg) have an average AUC of approximately about 80% of 165.4 μg·h/Lto about 125% of about 551.9 μg·h/L. The geometric mean AUC ofrivaroxaban for 2.5 mg dose of rivaroxaban is 165.4 μg·h/L to 551.9μg·h/L. Thus, consistent with Example 1, the blood plasma levels of apatient who is administered 1.75 mg of rivaroxaban and who isconcomitantly administered verapamil is approximately equal to those ofpatient who is administered 2.5 mg of rivaroxaban.

Example 5. Oral Verapamil, Aspirin, and Rivaroxaban Drug-DrugInteraction

Additional studies are performed to determine the presence of DDIs inpatients treated with oral verapamil, aspirin, and rivaroxaban. Thisstudy is performed through a University, Hospital, Clinic, or otherfacility with proper approvals and access to subjects and is performedto demonstrate the presence of DDIs. A representative example of such astudy is found in Example 1.

This study assesses the pharmacokinetic and pharmacodynamic consequencesof concomitant administration 0.5-2.5 mg of rivaroxaban, 100 mg ofaspirin, and recommended doses of verapamil in patients (e.g., healthyand renally impaired) by measuring blood plasma levels at various timeintervals after dosing. Patients are administered 0.5-2.5 mg ofrivaroxaban concomitantly with verapamil (100-480 mg), and blood plasmalevels are measured and compared to similar (e.g., identical) patientswho were not administered verapamil. Patents concomitantly treated withrivaroxaban and verapamil have a much higher plasma rivaroxaban levelthan for a similar (e.g., identical) patient who has not takenverapamil. Additionally, these studies show a linear relationshipbetween the pharmacokinetic and the pharmacodynamics of rivaroxaban insubjects with normal renal function and renal insufficiency.

This study also investigates the plasma levels of rivaroxaban and therisk of major bleeding in patients (e.g., healthy and renally impaired)in accordance with Example 1. This study, for example, examines thesteady state area under the curve (AUC) of plasma rivaroxaban insubjects with either normal renal function or renal impairment underdifferent treatment regimens.

This study shows that the concomitant administration of oral verapamil,aspirin, and rivaroxaban leads to a higher accumulation of rivaroxabanin the plasma, resulting in a significantly higher risk of majorbleeding compared to subjects not concomitantly administered verapamil.Additional outcomes include a linear relationship between the risk ofmajor bleeding in subjects with normal renal function and renalinsufficiency.

In one study, patients are administered a 2.5 mg dose of rivaroxaban andconcomitantly administered verapamil and aspirin (100 mg). The bloodplasma level of rivaroxaban for such a patient is equal to or greaterthan a similar patient who has taken a 5 mg dose of rivaroxaban and whohas not taken verapamil, and the risk of major bleeding is equal to orgreater than that measured for a similar patient who has taken a 5 mgdose of rivaroxaban and who has not taken verapamil. That is, theaverage geometric mean of subjects who take a single dose of rivaroxaban(e.g., 2.5 mg), and verapamil (e.g., 360 mg) has an average AUC ofapproximately 1064.25 μg·hr/L or greater and a risk of major bleeding ofnot more than about 4.5%, e.g., about 3% The geometric mean AUC ofrivaroxaban for 5 mg dose of rivaroxaban is 1064.25 μg·h/L. Thus,consistent with Example 1, the blood plasma levels of a patient who isadministered 2.5 mg of rivaroxaban and who is concomitantly administeredverapamil are approximately equal to those of patient who isadministered 5 mg of rivaroxaban.

In another study, patients are administered a 1.75 mg dose ofrivaroxaban and concomitantly administered verapamil. The blood plasmalevel of rivaroxaban for such a patient is approximately equal to asimilar patient who has taken a 2.5 mg dose of rivaroxaban and who hasnot taken verapamil and the risk of major bleeding is less than or equalto that measured for a similar patient who has taken a 5 mg dose ofrivaroxaban and who has not taken verapamil. That is, the averagegeometric mean of subjects who take a single dose of rivaroxaban (e.g.,1.75 mg) and verapamil (e.g., 360 mg) have an average AUC ofapproximately about 80% of 165.4 μg·h/L to about 125% of about 551.9μg·h/L, and a risk of major bleeding of not more than about 4.5%, e.g.,from about 1.5-2.0%. The geometric mean AUC of rivaroxaban for 2.5 mgdose of rivaroxaban is 165.4 μg·h/L to 551.9 μg·h/L. Thus, consistentwith Example 1, the blood plasma levels of a patient who is administered1.75 mg of rivaroxaban and who is concomitantly administered verapamilis approximately equal to those of a patient who is administered 2.5 mgof rivaroxaban.

While the invention has been described in connection with specificembodiments thereof, it will be understood that it is capable of furthermodifications and this application is intended to cover any variations,uses, or adaptations of the invention following, in general, theprinciples of the invention and including such departures from thepresent disclosure as come within known or customary practice within theart to which the invention pertains and as may be applied to theessential features hereinbefore set forth and as follows in the scope ofthe appended claims.

All references, articles, publications, patents, patent publications,and patent applications cited herein are incorporated by reference intheir entireties for all purposes.

However, mention of any reference, article, publication, patent, patentpublication, and patent application cited herein is not, and should notbe taken as, an acknowledgment or any form of suggestion that theyconstitute valid prior art or form part of the common general knowledgein any country in the world.

INCORPORATION BY REFERENCE

The following references are herein incorporated by reference in theirentireties:

-   1. Connolly et al., Lancet, 391: 205-18 (2018).-   2. Anand et al., Lancet, 391, 219-229, 20 (2018).-   3. Mega et al., N Engl J Med, 366:9-19 (2012).-   4. Correspondence for Rivaroxaban in Stable Cardiovascular Disease,    N Engl J Med, 378; 4 (2018).-   5. Eikelboom et al., N Engl J Med, 377:1319-30 (2017).-   6. US Patent Application Publication 2017/0239260 A1

1. A method of reducing the risk of stroke and systemic embolism inpatients with non valvular atrial fibrillation in a patient in need oftreatment with rivaroxaban and verapamil, comprising: (a) administeringabout 100 to about 480 mg verapamil daily to the patient; (b)administering about 75 mg to about 325 mg of aspirin to the patient; and(c) administering 1 mg to 15 mg of rivaroxaban to the patient; whereinthe patient has a creatinine clearance (CLCr) of >50 mL/min to 79mL/min.
 2. A method of treating deep vein thrombosis and pulmonaryembolism in a patient in need of treatment with rivaroxaban andverapamil, comprising: (a) administering about 100 to about 480 mgverapamil daily to the patient; (b) administering about 75 mg to about325 mg of aspirin to the patient; and (c) administering a daily dose of1 mg to 15 mg of rivaroxaban to the patient; wherein the patient has acreatinine clearance (CLCr) of >50 mL/min to 79 mL/min.
 3. A method ofreducing the risk of recurrence of deep vein thrombosis (DVT) andpulmonary embolism (PE), or the prophylaxis of deep vein thrombosis(DVT) and pulmonary embolism (PE) following hip or knee replacementsurgery, in a patient in need of treatment with rivaroxaban andverapamil, comprising: (a) administering about 100 to about 480 mgverapamil daily to the patient; and (b) administering about 75 mg toabout 325 mg of aspirin to the patient; and (c) administering a dailydose of 1 mg to 7.5 mg of rivaroxaban to the patient; wherein thepatient has a creatinine clearance (CLCr) of >50 mL/min to 79 mL/min. 4.The method of claim 1, wherein the dose of verapamil administered instep (a) is 120, 240, 360, or 480 mg.
 5. The method of claim 2, whereinthe dose of verapamil administered in step (a) is 120, 240, 360, or 480mg.
 6. The method of claim 3, wherein the dose of verapamil administeredin step (a) is 120, 240, 360, or 480 mg.
 7. The method of claim 1,wherein the dose of aspirin administered in step (b) is 100 mg.
 8. Themethod of claim 2, wherein the dose of aspirin administered in step (b)is 100 mg.
 9. The method of claim 3, wherein the dose of aspirinadministered in step (b) is 100 mg.
 10. The method of claim 1, whereinthe dose of rivaroxaban administered in step (c) ranges from about 5 mgto about 15 mg.
 11. The method of claim 1, wherein the dose ofrivaroxaban administered in step (c) is selected from the groupconsisting of about 1.75 mg, about 2.5 mg, about 5 mg, about 7 mg toabout 8 mg, about 10 mg, about 12 mg to about 13 mg, and about 15 mg.12. The method of claim 2, wherein the dose of rivaroxaban administeredin step (c) ranges from about 5 mg to about 15 mg.
 13. The method ofclaim 2, wherein the dose of rivaroxaban administered in step (c) isselected from the group consisting of about 1.75 mg, about 2.5 mg, about5 mg, about 7 mg to about 8 mg, about 10 mg, about 12 to about 13 mg,and about 15 mg.
 14. The method of claim 3, wherein the dose ofrivaroxaban administered in step (c) is selected from the groupconsisting of about 1.75 mg, about 2.5 mg, about 5 mg, and about 7 mg toabout 8 mg.
 15. The method of claim 2, wherein the patient isadministered the dose rivaroxaban twice daily.
 16. The method of claim2, wherein the patient is administered the dose of rivaroxaban oncedaily.
 17. The method of claim 1, wherein the patient is administeredthe dose of rivaroxaban once daily.
 18. The method of claim 3, whereinthe patient is administered the dose of rivaroxaban once daily.